Journal: Nat Med

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Abstract

Sex differences in cardiometabolic disorders.

Gerdts E, Regitz-Zagrosek V

The prevalence of cardiometabolic disorders in both women and men has increased worldwide and is linked to a rise in obesity and obesity-associated associated clustering of other cardiometabolic risk factors such as hypertension, impaired glucose regulation and dyslipidemia. However, the predominance of common types of cardiometabolic disorders such as heart failure, atrial fibrillation and ischemic heart disease is sex specific, and our identification of these and the underlying mechanisms is only just emerging. New evidence suggests that sex hormones, sex-specific molecular mechanisms and gender influence glucose and lipid metabolisms, as well as cardiac energy metabolism, and function. Here we review sex differences in cardiometabolic risk factors, associated preclinical and clinical cardiac disorders and potential therapeutic avenues.



Nat Med: 06 Nov 2019; epub ahead of print
Gerdts E, Regitz-Zagrosek V
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700185
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Abstract

Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells.

Frodermann V, Rohde D, Courties G, Severe N, ... Swirski FK, Nahrendorf M

A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creER; Lepr mice reveals that leptin\'s effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.



Nat Med: 06 Nov 2019; epub ahead of print
Frodermann V, Rohde D, Courties G, Severe N, ... Swirski FK, Nahrendorf M
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700184
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Abstract

Understanding the rise of cardiometabolic diseases in low- and middle-income countries.

Miranda JJ, Barrientos-Gutiérrez T, Corvalan C, Hyder AA, ... Oni T, Wells JCK

Increases in the prevalence of noncommunicable diseases (NCDs), particularly cardiometabolic diseases such as cardiovascular disease, stroke and diabetes, and their major risk factors have not been uniform across settings: for example, cardiovascular disease mortality has declined over recent decades in high-income countries but increased in low- and middle-income countries (LMICs). The factors contributing to this rise are varied and are influenced by environmental, social, political and commercial determinants of health, among other factors. This Review focuses on understanding the rise of cardiometabolic diseases in LMICs, with particular emphasis on obesity and its drivers, together with broader environmental and macro determinants of health, as well as LMIC-based responses to counteract cardiometabolic diseases.



Nat Med: 06 Nov 2019; epub ahead of print
Miranda JJ, Barrientos-Gutiérrez T, Corvalan C, Hyder AA, ... Oni T, Wells JCK
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700182
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Abstract

Glomerular filtration rate by differing measures, albuminuria and prediction of cardiovascular disease, mortality and end-stage kidney disease.

Lees JS, Welsh CE, Celis-Morales CA, Mackay D, ... Welsh P, Mark PB

Chronic kidney disease is common in the general population and associated with excess cardiovascular disease (CVD), but kidney function does not feature in current CVD risk-prediction models. We tested three formulae for estimated glomerular filtration rate (eGFR) to determine which was the most clinically informative for predicting CVD and mortality. Using data from 440,526 participants from UK Biobank, eGFR was calculated using serum creatinine, cystatin C (eGFRcys) and creatinine-cystatin C. Associations of each eGFR with CVD outcome and mortality were compared using Cox models and adjusting for atherosclerotic risk factors (per relevant risk scores), and the predictive utility was determined by the C-statistic and categorical net reclassification index. We show that eGFRcys is most strongly associated with CVD and mortality, and, along with albuminuria, adds predictive discrimination to current CVD risk scores, whilst traditional creatinine-based measures are weakly associated with risk. Clinicians should consider measuring eGFRcys as part of cardiovascular risk assessment.



Nat Med: 06 Nov 2019; epub ahead of print
Lees JS, Welsh CE, Celis-Morales CA, Mackay D, ... Welsh P, Mark PB
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700174
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Abstract

Single-cell immune landscape of human atherosclerotic plaques.

Fernandez DM, Rahman AH, Fernandez NF, Chudnovskiy A, ... Merad M, Giannarelli C

Atherosclerosis is driven by multifaceted contributions of the immune system within the circulation and at vascular focal sites. However, specific characteristics of dysregulated immune cells within atherosclerotic lesions that lead to clinical events such as ischemic stroke or myocardial infarction are poorly understood. Here, using single-cell proteomic and transcriptomic analyses, we uncovered distinct features of both T cells and macrophages in carotid artery plaques of patients with clinically symptomatic disease (recent stroke or transient ischemic attack) compared to asymptomatic disease (no recent stroke). Plaques from symptomatic patients were characterized by a distinct subset of CD4 T cells and by T cells that were activated and differentiated. Moreover, some T cell subsets in these plaques presented markers of T cell exhaustion. Additionally, macrophages from these plaques contained alternatively activated phenotypes, including subsets associated with plaque vulnerability. In plaques from asymptomatic patients, T cells and macrophages were activated and displayed evidence of interleukin-1β signaling. The identification of specific features of innate and adaptive immune cells in plaques that are associated with cerebrovascular events may enable the design of more precisely tailored cardiovascular immunotherapies.



Nat Med: 06 Oct 2019; epub ahead of print
Fernandez DM, Rahman AH, Fernandez NF, Chudnovskiy A, ... Merad M, Giannarelli C
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591603
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Abstract

Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study.

Staaf J, Glodzik D, Bosch A, Vallon-Christersson J, ... Borg Ã…, Nik-Zainal S

Whole-genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore the clinical value of WGS, we sequenced 254 triple-negative breast cancers (TNBCs) for which associated treatment and outcome data were collected between 2010 and 2015 via the population-based Sweden Cancerome Analysis Network-Breast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. HRDetect provided independent prognostic information, with HRDetect-high patients having better outcome on adjuvant chemotherapy for invasive disease-free survival (hazard ratio (HR) = 0.42; 95% confidence interval (CI) = 0.2-0.87) and distant relapse-free interval (HR = 0.31, CI = 0.13-0.76) compared to HRDetect-low, regardless of whether a genetic/epigenetic cause was identified. HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had the poorest outcomes. HRDetect-low cancers also had inadequate outcomes: ~4.7% were mismatch-repair-deficient (another targetable defect, not typically sought) and they were enriched for (but not restricted to) PIK3CA/AKT1 pathway abnormalities. New treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making.



Nat Med: 29 Sep 2019; epub ahead of print
Staaf J, Glodzik D, Bosch A, Vallon-Christersson J, ... Borg Ã…, Nik-Zainal S
Nat Med: 29 Sep 2019; epub ahead of print | PMID: 31570822
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Abstract

Around the world and back again.

Loi S

Sherene Loi is a medical oncologist and clinician scientist at the Peter MacCallum Cancer Centre in Melbourne, Australia. Her laboratory studies the cancer genome in breast cancer and its interface with the immune microenvironment in order to develop more effective drugs and rational combinations.



Nat Med: 06 Oct 2019; epub ahead of print
Loi S
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591582
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Abstract

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Schubert RD, Hawes IA, Ramachandran PS, Ramesh A, ... DeRisi JL, Wilson MR

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM). Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF). CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM.



Nat Med: 20 Oct 2019; epub ahead of print
Schubert RD, Hawes IA, Ramachandran PS, Ramesh A, ... DeRisi JL, Wilson MR
Nat Med: 20 Oct 2019; epub ahead of print | PMID: 31636453
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Abstract

A clonal expression biomarker associates with lung cancer mortality.

Biswas D, Birkbak NJ, Rosenthal R, Hiley CT, ... Swanton C,

An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types. Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.



Nat Med: 06 Oct 2019; epub ahead of print
Biswas D, Birkbak NJ, Rosenthal R, Hiley CT, ... Swanton C,
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591602
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Abstract

Preventing dysbiosis of the neonatal mouse intestinal microbiome protects against late-onset sepsis.

Singer JR, Blosser EG, Zindl CL, Silberger DJ, ... Randolph DA, Weaver CT

Late-onset sepsis (LOS) is thought to result from systemic spread of commensal microbes from the intestines of premature infants. Clinical use of probiotics for LOS prophylaxis has varied owing to limited efficacy, reflecting an incomplete understanding of relationships between development of the intestinal microbiome, neonatal dysbiosis and LOS. Using a model of LOS, we found that components of the developing microbiome were both necessary and sufficient to prevent LOS. Maternal antibiotic exposure that eradicated or enriched transmission of Lactobacillus murinus exacerbated and prevented disease, respectively. Prophylactic administration of some, but not all Lactobacillus spp. was protective, as was administration of Escherichia coli. Intestinal oxygen level was a major driver of colonization dynamics, albeit via mechanisms distinct from those in adults. These results establish a link between neonatal dysbiosis and LOS, and provide a basis for rational selection of probiotics that modulate primary succession of the microbiome to prevent disease.



Nat Med: 06 Nov 2019; epub ahead of print
Singer JR, Blosser EG, Zindl CL, Silberger DJ, ... Randolph DA, Weaver CT
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700190
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Abstract

Chromatin regulators mediate anthracycline sensitivity in breast cancer.

Seoane JA, Kirkland JG, Caswell-Jin JL, Crabtree GR, Curtis C

Anthracyclines are a highly effective component of curative breast cancer chemotherapy but are associated with substantial morbidity. Because anthracyclines work in part by inhibiting topoisomerase-II (TOP2) on accessible DNA, we hypothesized that chromatin regulatory genes (CRGs) that mediate DNA accessibility might predict anthracycline response. We studied the role of CRGs in anthracycline sensitivity in breast cancer through integrative analysis of patient and cell line data. We identified a consensus set of 38 CRGs associated with anthracycline response across ten cell line datasets. By evaluating the interaction between expression and treatment in predicting survival in a metacohort of 1006 patients with early-stage breast cancer, we identified 54 CRGs whose expression levels dictate anthracycline benefit across the clinical subgroups; of these CRGs, 12 overlapped with those identified in vitro. CRGs that promote DNA accessibility, including Trithorax complex members, were associated with anthracycline sensitivity when highly expressed, whereas CRGs that reduce accessibility, such as Polycomb complex proteins, were associated with decreased anthracycline sensitivity. We show that KDM4B modulates TOP2 accessibility to chromatin, elucidating a mechanism of TOP2 inhibitor sensitivity. These findings indicate that CRGs mediate anthracycline benefit by altering DNA accessibility, with implications for the stratification of patients with breast cancer and treatment decision making.



Nat Med: 06 Nov 2019; epub ahead of print
Seoane JA, Kirkland JG, Caswell-Jin JL, Crabtree GR, Curtis C
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700186
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Abstract

Adipsin preserves beta cells in diabetic mice and associates with protection from type 2 diabetes in humans.

Gómez-Banoy N, Guseh JS, Li G, Rubio-Navarro A, ... Ho JE, Lo JC

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.



Nat Med: 06 Nov 2019; epub ahead of print
Gómez-Banoy N, Guseh JS, Li G, Rubio-Navarro A, ... Ho JE, Lo JC
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700183
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Abstract

Expansion of primitive human hematopoietic stem cells by culture in a zwitterionic hydrogel.

Bai T, Li J, Sinclair A, Imren S, ... Jiang S, Delaney C

The ability to expand hematopoietic stem and progenitor cells (HSPCs) ex vivo is critical to fully realize the potential of HSPC-based therapies. In particular, the application of clinically effective therapies, such as cord blood transplantation, has been impeded because of limited HSPC availability. Here, using 3D culture of human HSPCs in a degradable zwitterionic hydrogel, we achieved substantial expansion of phenotypically primitive CD34 cord blood and bone-marrow-derived HSPCs. This culture system led to a 73-fold increase in long-term hematopoietic stem cell (LT-HSC) frequency, as demonstrated by limiting dilution assays, and the expanded HSPCs were capable of hematopoietic reconstitution for at least 24 weeks in immunocompromised mice. Both the zwitterionic characteristics of the hydrogel and the 3D format were important for HSPC self-renewal. Mechanistically, the impact of 3D zwitterionic hydrogel culture on mitigating HSPC differentiation and promoting self-renewal might result from an inhibition of excessive reactive oxygen species (ROS) production via suppression of O-related metabolism. HSPC expansion using zwitterionic hydrogels has the potential to facilitate the clinical application of hematopoietic-stem-cell therapies.



Nat Med: 06 Oct 2019; epub ahead of print
Bai T, Li J, Sinclair A, Imren S, ... Jiang S, Delaney C
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591594
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Abstract

Therapeutic inhibition of mTORC2 rescues the behavioral and neurophysiological abnormalities associated with Pten-deficiency.

Chen CJ, Sgritta M, Mays J, Zhou H, ... Noebels JL, Costa-Mattioli M

Dysregulation of the mammalian target of rapamycin (mTOR) signaling, which is mediated by two structurally and functionally distinct complexes, mTORC1 and mTORC2, has been implicated in several neurological disorders. Individuals carrying loss-of-function mutations in the phosphatase and tensin homolog (PTEN) gene, a negative regulator of mTOR signaling, are prone to developing macrocephaly, autism spectrum disorder (ASD), seizures and intellectual disability. It is generally believed that the neurological symptoms associated with loss of PTEN and other mTORopathies (for example, mutations in the tuberous sclerosis genes TSC1 or TSC2) are due to hyperactivation of mTORC1-mediated protein synthesis. Using molecular genetics, we unexpectedly found that genetic deletion of mTORC2 (but not mTORC1) activity prolonged lifespan, suppressed seizures, rescued ASD-like behaviors and long-term memory, and normalized metabolic changes in the brain of mice lacking Pten. In a more therapeutically oriented approach, we found that administration of an antisense oligonucleotide (ASO) targeting mTORC2\'s defining component Rictor specifically inhibits mTORC2 activity and reverses the behavioral and neurophysiological abnormalities in adolescent Pten-deficient mice. Collectively, our findings indicate that mTORC2 is the major driver underlying the neuropathophysiology associated with Pten-deficiency, and its therapeutic reduction could represent a promising and broadly effective translational therapy for neurological disorders where mTOR signaling is dysregulated.



Nat Med: 20 Oct 2019; epub ahead of print
Chen CJ, Sgritta M, Mays J, Zhou H, ... Noebels JL, Costa-Mattioli M
Nat Med: 20 Oct 2019; epub ahead of print | PMID: 31636454
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Abstract

A rectal cancer organoid platform to study individual responses to chemoradiation.

Ganesh K, Wu C, O\'Rourke KP, Szeglin BC, ... Sawyers CL, Smith JJ

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients\' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.



Nat Med: 06 Oct 2019; epub ahead of print
Ganesh K, Wu C, O'Rourke KP, Szeglin BC, ... Sawyers CL, Smith JJ
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591597
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Abstract

Vaginal microbiome transplantation in women with intractable bacterial vaginosis.

Lev-Sagie A, Goldman-Wohl D, Cohen Y, Dori-Bachash M, ... Yagel S, Elinav E

We report the results of a first exploratory study testing the use of vaginal microbiome transplantation (VMT) from healthy donors as a therapeutic alternative for patients suffering from symptomatic, intractable and recurrent bacterial vaginosis (ClinicalTrials.gov NCT02236429 ). In our case series, five patients were treated, and in four of them VMT was associated with full long-term remission until the end of follow-up at 5-21 months after VMT, defined as marked improvement of symptoms, Amsel criteria, microscopic vaginal fluid appearance and reconstitution of a Lactobacillus-dominated vaginal microbiome. One patient presented with incomplete remission in clinical and laboratory features. No adverse effects were observed in any of the five women. Notably, remission in three patients necessitated repeated VMT, including a donor change in one patient, to elicit a long-standing clinical response. The therapeutic efficacy of VMT in women with intractable and recurrent bacterial vaginosis should be further determined in randomized, placebo-controlled clinical trials.



Nat Med: 06 Oct 2019; epub ahead of print
Lev-Sagie A, Goldman-Wohl D, Cohen Y, Dori-Bachash M, ... Yagel S, Elinav E
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591599
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Abstract

Genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in ICU patients.

Yelin I, Flett KB, Merakou C, Mehrotra P, ... Kishony R, Priebe GP

Probiotics are routinely administered to hospitalized patients for many potential indications but have been associated with adverse effects that may outweigh their potential benefits. It is particularly alarming that probiotic strains can cause bacteremia, yet direct evidence for an ancestral link between blood isolates and administered probiotics is lacking. Here we report a markedly higher risk of Lactobacillus bacteremia for intensive care unit (ICU) patients treated with probiotics compared to those not treated, and provide genomics data that support the idea of direct clonal transmission of probiotics to the bloodstream. Whole-genome-based phylogeny showed that Lactobacilli isolated from treated patients\' blood were phylogenetically inseparable from Lactobacilli isolated from the associated probiotic product. Indeed, the minute genetic diversity among the blood isolates mostly mirrored pre-existing genetic heterogeneity found in the probiotic product. Some blood isolates also contained de novo mutations, including a non-synonymous SNP conferring antibiotic resistance in one patient. Our findings support that probiotic strains can directly cause bacteremia and adaptively evolve within ICU patients.



Nat Med: 06 Nov 2019; epub ahead of print
Yelin I, Flett KB, Merakou C, Mehrotra P, ... Kishony R, Priebe GP
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700189
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Abstract

Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy.

Chowell D, Krishna C, Pierini F, Makarov V, ... Lenz TL, Chan TA

Functional diversity of the highly polymorphic human leukocyte antigen class I (HLA-I) genes underlies successful immunologic control of both infectious disease and cancer. The divergent allele advantage hypothesis dictates that an HLA-I genotype with two alleles with sequences that are more divergent enables presentation of more diverse immunopeptidomes. However, the effect of sequence divergence between HLA-I alleles-a quantifiable measure of HLA-I evolution-on the efficacy of immune checkpoint inhibitor (ICI) treatment for cancer remains unknown. In the present study the germline HLA-I evolutionary divergence (HED) of patients with cancer treated with ICIs was determined by quantifying the physiochemical sequence divergence between HLA-I alleles of each patient\'s genotype. HED was a strong determinant of survival after treatment with ICIs. Even among patients fully heterozygous at HLA-I, patients with an HED in the upper quartile respond better to ICIs than patients with a low HED. Furthermore, HED strongly impacts the diversity of tumor, viral and self-immunopeptidomes and intratumoral T cell receptor clonality. Similar to tumor mutation burden, HED is a fundamental metric of diversity at the major histocompatibility complex-peptide complex, which dictates ICI efficacy. The data link divergent HLA allele advantage to immunotherapy efficacy and unveil how ICI response relies on the evolved efficiency of HLA-mediated immunity.



Nat Med: 06 Nov 2019; epub ahead of print
Chowell D, Krishna C, Pierini F, Makarov V, ... Lenz TL, Chan TA
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700181
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Abstract

Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension.

Baron M, Maillet J, Huyvaert M, Dechaume A, ... Froguel P, Bonnefond A

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor. Although some MRAP2 mutations have been described in people with obesity, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.



Nat Med: 06 Nov 2019; epub ahead of print
Baron M, Maillet J, Huyvaert M, Dechaume A, ... Froguel P, Bonnefond A
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700171
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Abstract

Developing neoantigen-targeted T cell-based treatments for solid tumors.

Yamamoto TN, Kishton RJ, Restifo NP

Stimulating an immune response against cancer through adoptive transfer of tumor-targeting lymphocytes has shown great promise in hematological malignancies, but clinical efficacy against many common solid epithelial cancers remains low. Targeting \'neoantigens\'-the somatic mutations expressed only by tumor cells-might enable tumor destruction without causing undue damage to vital healthy tissues. Major challenges to targeting neoantigens with T cells include heterogeneity and variability in antigen processing and presentation of targets by tumors, and an incomplete understanding of which T cell qualities are essential for clinically effective therapies. Finally, the prospect of targeting somatic tumor mutations to promote T cell destruction of cancer must contend with the biology that not all tumor-expressed \'neoepitopes\' actually generate neoantigens that can be functionally recognized and provoke an effective immune response. In this Review, we discuss the promise, progress and challenges for improving neoantigen-targeted T cell-based immunotherapies for cancer.



Nat Med: 06 Oct 2019; epub ahead of print
Yamamoto TN, Kishton RJ, Restifo NP
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591590
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Abstract

Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer.

Joshi K, Robert de Massy M, Ismail M, Reading JL, ... Quezada SA, Chain B

Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8 tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.



Nat Med: 03 Oct 2019; epub ahead of print
Joshi K, Robert de Massy M, Ismail M, Reading JL, ... Quezada SA, Chain B
Nat Med: 03 Oct 2019; epub ahead of print | PMID: 31591606
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Abstract

Contribution of genetics to visceral adiposity and its relation to cardiovascular and metabolic disease.

Karlsson T, Rask-Andersen M, Pan G, Höglund J, ... Ek WE, Johansson Å

Visceral adipose tissue (VAT)-fat stored around the internal organs-has been suggested as an independent risk factor for cardiovascular and metabolic disease, as well as all-cause, cardiovascular-specific and cancer-specific mortality. Yet, the contribution of genetics to VAT, as well as its disease-related effects, are largely unexplored due to the requirement for advanced imaging technologies to accurately measure VAT. Here, we develop sex-stratified, nonlinear prediction models (coefficient of determination = 0.76; typical 95% confidence interval (CI) = 0.74-0.78) for VAT mass using the UK Biobank cohort. We performed a genome-wide association study for predicted VAT mass and identified 102 novel visceral adiposity loci. Predicted VAT mass was associated with increased risk of hypertension, heart attack/angina, type 2 diabetes and hyperlipidemia, and Mendelian randomization analysis showed visceral fat to be a causal risk factor for all four diseases. In particular, a large difference in causal effect between the sexes was found for type 2 diabetes, with an odds ratio of 7.34 (95% CI = 4.48-12.0) in females and an odds ratio of 2.50 (95% CI = 1.98-3.14) in males. Our findings bolster the role of visceral adiposity as a potentially independent risk factor, in particular for type 2 diabetes in Caucasian females. Independent validation in other cohorts is necessary to determine whether the findings can translate to other ethnicities, or outside the UK.



Nat Med: 30 Aug 2019; 25:1390-1395
Karlsson T, Rask-Andersen M, Pan G, Höglund J, ... Ek WE, Johansson Å
Nat Med: 30 Aug 2019; 25:1390-1395 | PMID: 31501611
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Impact:
Abstract

Deep learning-based classification of mesothelioma improves prediction of patient outcome.

Courtiol P, Maussion C, Moarii M, Pronier E, ... Wainrib G, Clozel T

Malignant mesothelioma (MM) is an aggressive cancer primarily diagnosed on the basis of histological criteria. The 2015 World Health Organization classification subdivides mesothelioma tumors into three histological types: epithelioid, biphasic and sarcomatoid MM. MM is a highly complex and heterogeneous disease, rendering its diagnosis and histological typing difficult and leading to suboptimal patient care and decisions regarding treatment modalities. Here we have developed a new approach-based on deep convolutional neural networks-called MesoNet to accurately predict the overall survival of mesothelioma patients from whole-slide digitized images, without any pathologist-provided locally annotated regions. We validated MesoNet on both an internal validation cohort from the French MESOBANK and an independent cohort from The Cancer Genome Atlas (TCGA). We also demonstrated that the model was more accurate in predicting patient survival than using current pathology practices. Furthermore, unlike classical black-box deep learning methods, MesoNet identified regions contributing to patient outcome prediction. Strikingly, we found that these regions are mainly located in the stroma and are histological features associated with inflammation, cellular diversity and vacuolization. These findings suggest that deep learning models can identify new features predictive of patient survival and potentially lead to new biomarker discoveries.



Nat Med: 06 Oct 2019; epub ahead of print
Courtiol P, Maussion C, Moarii M, Pronier E, ... Wainrib G, Clozel T
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591589
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Abstract

A library of human gut bacterial isolates paired with longitudinal multiomics data enables mechanistic microbiome research.

Poyet M, Groussin M, Gibbons SM, Avila-Pacheco J, ... Xavier RJ, Alm EJ

Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used \'omics\' survey methods are more reliable when using averages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels, and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research.



Nat Med: 30 Aug 2019; 25:1442-1452
Poyet M, Groussin M, Gibbons SM, Avila-Pacheco J, ... Xavier RJ, Alm EJ
Nat Med: 30 Aug 2019; 25:1442-1452 | PMID: 31477907
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Abstract

A framework for the investigation of rare genetic disorders in neuropsychiatry.

Sanders SJ, Sahin M, Hostyk J, Thurm A, ... Gur RE, Bearden CE

De novo and inherited rare genetic disorders (RGDs) are a major cause of human morbidity, frequently involving neuropsychiatric symptoms. Recent advances in genomic technologies and data sharing have revolutionized the identification and diagnosis of RGDs, presenting an opportunity to elucidate the mechanisms underlying neuropsychiatric disorders by investigating the pathophysiology of high-penetrance genetic risk factors. Here we seek out the best path forward for achieving these goals. We think future research will require consistent approaches across multiple RGDs and developmental stages, involving both the characterization of shared neuropsychiatric dimensions in humans and the identification of neurobiological commonalities in model systems. A coordinated and concerted effort across patients, families, researchers, clinicians and institutions, including rapid and broad sharing of data, is now needed to translate these discoveries into urgently needed therapies.



Nat Med: 29 Sep 2019; 25:1477-1487
Sanders SJ, Sahin M, Hostyk J, Thurm A, ... Gur RE, Bearden CE
Nat Med: 29 Sep 2019; 25:1477-1487 | PMID: 31548702
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Abstract

Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia.

Río P, Navarro S, Wang W, Sánchez-Domínguez R, ... Sevilla J, Bueren JA

Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 22 FA genes discovered to date. Mutations in FANCA account for more than 60% of FA cases worldwide. Clinically, FA is associated with congenital abnormalities and cancer predisposition. However, bone marrow failure is the primary pathological feature of FA that becomes evident in 70-80% of patients with FA during the first decade of life. In this clinical study (ClinicalTrials.gov, NCT03157804 ; European Clinical Trials Database, 2011-006100-12), we demonstrate that lentiviral-mediated hematopoietic gene therapy reproducibly confers engraftment and proliferation advantages of gene-corrected hematopoietic stem cells (HSCs) in non-conditioned patients with FA subtype A. Insertion-site analyses revealed the multipotent nature of corrected HSCs and showed that the repopulation advantage of these cells was not due to genotoxic integrations of the therapeutic provirus. Phenotypic correction of blood and bone marrow cells was shown by the acquired resistance of hematopoietic progenitors and T lymphocytes to DNA cross-linking agents. Additionally, an arrest of bone marrow failure progression was observed in patients with the highest levels of gene marking. The progressive engraftment of corrected HSCs in non-conditioned patients with FA supports that gene therapy should constitute an innovative low-toxicity therapeutic option for this life-threatening disorder.



Nat Med: 30 Aug 2019; 25:1396-1401
Río P, Navarro S, Wang W, Sánchez-Domínguez R, ... Sevilla J, Bueren JA
Nat Med: 30 Aug 2019; 25:1396-1401 | PMID: 31501599
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Abstract

Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse.

Chemi F, Rothwell DG, McGranahan N, Gulati S, ... Dive C,

Approximately 50% of patients with early-stage non-small-cell lung cancer (NSCLC) who undergo surgery with curative intent will relapse within 5 years. Detection of circulating tumor cells (CTCs) at the time of surgery may represent a tool to identify patients at higher risk of recurrence for whom more frequent monitoring is advised. Here we asked whether CellSearch-detected pulmonary venous CTCs (PV-CTCs) at surgical resection of early-stage NSCLC represent subclones responsible for subsequent disease relapse. PV-CTCs were detected in 48% of 100 patients enrolled into the TRACERx study, were associated with lung-cancer-specific relapse and remained an independent predictor of relapse in multivariate analysis adjusted for tumor stage. In a case study, genomic profiling of single PV-CTCs collected at surgery revealed higher mutation overlap with metastasis detected 10 months later (91%) than with the primary tumor (79%), suggesting that early-disseminating PV-CTCs were responsible for disease relapse. Together, PV-CTC enumeration and genomic profiling highlight the potential of PV-CTCs as early predictors of NSCLC recurrence after surgery. However, the limited sensitivity of PV-CTCs in predicting relapse suggests that further studies using a larger, independent cohort are warranted to confirm and better define the potential clinical utility of PV-CTCs in early-stage NSCLC.



Nat Med: 06 Oct 2019; epub ahead of print
Chemi F, Rothwell DG, McGranahan N, Gulati S, ... Dive C,
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591595
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Impact:
Abstract

Safety profile of autologous macrophage therapy for liver cirrhosis.

Moroni F, Dwyer BJ, Graham C, Pass C, ... Fallowfield JA, Forbes SJ

Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups of three participants received a single peripheral infusion of 10, 10 or up to 10 cells. Leukapheresis and macrophage infusion were well tolerated with no transfusion reactions, dose-limiting toxicities or macrophage activation syndrome. All participants were alive and transplant-free at one year, with only one clinical event recorded, the occurrence of minimal ascites. The primary outcomes of safety and feasibility were met. This study informs and provides a rationale for efficacy studies in cirrhosis and other fibrotic diseases.



Nat Med: 06 Oct 2019; epub ahead of print
Moroni F, Dwyer BJ, Graham C, Pass C, ... Fallowfield JA, Forbes SJ
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591593
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Impact:
Abstract

Genome-wide germline correlates of the epigenetic landscape of prostate cancer.

Houlahan KE, Shiah YJ, Gusev A, Yuan J, ... Bristow RG, Boutros PC

Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor\'s epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.



Nat Med: 06 Oct 2019; epub ahead of print
Houlahan KE, Shiah YJ, Gusev A, Yuan J, ... Bristow RG, Boutros PC
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591588
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Impact:
Abstract

Avoidable flaws in observational analyses: an application to statins and cancer.

Dickerman BA, García-Albéniz X, Logan RW, Denaxas S, Hernán MA

The increasing availability of large healthcare databases is fueling an intense debate on whether real-world data should play a role in the assessment of the benefit-risk of medical treatments. In many observational studies, for example, statin users were found to have a substantially lower risk of cancer than in meta-analyses of randomized trials. Although such discrepancies are often attributed to a lack of randomization in the observational studies, they might be explained by flaws that can be avoided by explicitly emulating a target trial (the randomized trial that would answer the question of interest). Using the electronic health records of 733,804 UK adults, we emulated a target trial of statins and cancer and compared our estimates with those obtained using previously applied analytic approaches. Over the 10-yr follow-up, 28,408 individuals developed cancer. Under the target trial approach, estimated observational analogs of intention-to-treat and per-protocol 10-yr cancer-free survival differences were -0.5% (95% confidence interval (CI) -1.0%, 0.0%) and -0.3% (95% CI -1.5%, 0.5%), respectively. By contrast, previous analytic approaches yielded estimates that appeared to be strongly protective. Our findings highlight the importance of explicitly emulating a target trial to reduce bias in the effect estimates derived from observational analyses.



Nat Med: 06 Oct 2019; epub ahead of print
Dickerman BA, García-Albéniz X, Logan RW, Denaxas S, Hernán MA
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591592
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Impact:
Abstract

Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models.

Song Y, Morales L, Malik AS, Mead AF, ... Kornegay JN, Stedman HH

The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin, a rod-like protein that protects striated myocytes from contraction-induced injury. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin. Importantly, normal thymic expression in DMD patients should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (µUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that µUtro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-µUtro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, µUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of µUtro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed µDystrophin (µDystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization.



Nat Med: 06 Oct 2019; epub ahead of print
Song Y, Morales L, Malik AS, Mead AF, ... Kornegay JN, Stedman HH
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591596
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Impact:
Abstract

A luminal unfolding microneedle injector for oral delivery of macromolecules.

Abramson A, Caffarel-Salvador E, Soares V, Minahan D, ... Langer R, Traverso G

Insulin and other injectable biologic drugs have transformed the treatment of patients suffering from diabetes, yet patients and healthcare providers often prefer to use and prescribe less effective orally dosed medications. Compared with subcutaneously administered drugs, oral formulations create less patient discomfort, show greater chemical stability at high temperatures, and do not generate biohazardous needle waste. An oral dosage form for biologic medications is ideal; however, macromolecule drugs are not readily absorbed into the bloodstream through the gastrointestinal tract. We developed an ingestible capsule, termed the luminal unfolding microneedle injector, which allows for the oral delivery of biologic drugs by rapidly propelling dissolvable drug-loaded microneedles into intestinal tissue using a set of unfolding arms. During ex vivo human and in vivo swine studies, the device consistently delivered the microneedles to the tissue without causing complete thickness perforations. Using insulin as a model drug, we showed that, when actuated, the luminal unfolding microneedle injector provided a faster pharmacokinetic uptake profile and a systemic uptake >10% of that of a subcutaneous injection over a 4-h sampling period. With the ability to load a multitude of microneedle formulations, the device can serve as a platform to orally deliver therapeutic doses of macromolecule drugs.



Nat Med: 06 Oct 2019; epub ahead of print
Abramson A, Caffarel-Salvador E, Soares V, Minahan D, ... Langer R, Traverso G
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591601
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Impact:
Abstract

Generation of functional lungs via conditional blastocyst complementation using pluripotent stem cells.

Mori M, Furuhashi K, Danielsson JA, Hirata Y, ... Nakauchi H, Cardoso WV

Millions of people worldwide with incurable end-stage lung disease die because of inadequate treatment options and limited availability of donor organs for lung transplantation. Current bioengineering strategies to regenerate the lung have not been able to replicate its extraordinary cellular diversity and complex three-dimensional arrangement, which are indispensable for life-sustaining gas exchange. Here we report the successful generation of functional lungs in mice through a conditional blastocyst complementation (CBC) approach that vacates a specific niche in chimeric hosts and allows for initiation of organogenesis by donor mouse pluripotent stem cells (PSCs). We show that wild-type donor PSCs rescued lung formation in genetically defective recipient mouse embryos unable to specify (due to Ctnnb1 mutation) or expand (due to Fgfr2 mutation) early respiratory endodermal progenitors. Rescued neonates survived into adulthood and had lungs functionally indistinguishable from those of wild-type littermates. Efficient chimera formation and lung complementation required newly developed culture conditions that maintained the developmental potential of the donor PSCs and were associated with global DNA hypomethylation and increased H4 histone acetylation. These results pave the way for the development of new strategies for generating lungs in large animals to enable modeling of human lung disease as well as cell-based therapeutic interventions.



Nat Med: 06 Nov 2019; epub ahead of print
Mori M, Furuhashi K, Danielsson JA, Hirata Y, ... Nakauchi H, Cardoso WV
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700187
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Impact:
Abstract

Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV.

Ehrhardt SA, Zehner M, Krähling V, Cohen-Dvashi H, ... Becker S, Klein F

Recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) is the most advanced Ebola virus vaccine candidate and is currently being used to combat the outbreak of Ebola virus disease (EVD) in the Democratic Republic of the Congo (DRC). Here we examine the humoral immune response in a subset of human volunteers enrolled in a phase 1 rVSV-ZEBOV vaccination trial by performing comprehensive single B cell and electron microscopy structure analyses. Four studied vaccinees show polyclonal, yet reproducible and convergent B cell responses with shared sequence characteristics. EBOV-targeting antibodies cross-react with other Ebolavirus species, and detailed epitope mapping revealed overlapping target epitopes with antibodies isolated from EVD survivors. Moreover, in all vaccinees, we detected highly potent EBOV-neutralizing antibodies with activities comparable or superior to the monoclonal antibodies currently used in clinical trials. These include antibodies combining the IGHV3-15/IGLV1-40 immunoglobulin gene segments that were identified in all investigated individuals. Our findings will help to evaluate and direct current and future vaccination strategies and offer opportunities for novel EVD therapies.



Nat Med: 06 Oct 2019; epub ahead of print
Ehrhardt SA, Zehner M, Krähling V, Cohen-Dvashi H, ... Becker S, Klein F
Nat Med: 06 Oct 2019; epub ahead of print | PMID: 31591605
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Impact:
Abstract

Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers.

Parikh AR, Leshchiner I, Elagina L, Goyal L, ... Getz G, Corcoran RB

During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the \'rule\' rather than the \'exception\'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.



Nat Med: 30 Aug 2019; 25:1415-1421
Parikh AR, Leshchiner I, Elagina L, Goyal L, ... Getz G, Corcoran RB
Nat Med: 30 Aug 2019; 25:1415-1421 | PMID: 31501609
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Impact:
Abstract

Sensory feedback restoration in leg amputees improves walking speed, metabolic cost and phantom pain.

Petrini FM, Bumbasirevic M, Valle G, Ilic V, ... Micera S, Raspopovic S

Conventional leg prostheses do not convey sensory information about motion or interaction with the ground to above-knee amputees, thereby reducing confidence and walking speed in the users that is associated with high mental and physical fatigue. The lack of physiological feedback from the remaining extremity to the brain also contributes to the generation of phantom limb pain from the missing leg. To determine whether neural sensory feedback restoration addresses these issues, we conducted a study with two transfemoral amputees, implanted with four intraneural stimulation electrodes in the remaining tibial nerve (ClinicalTrials.gov identifier NCT03350061). Participants were evaluated while using a neuroprosthetic device consisting of a prosthetic leg equipped with foot and knee sensors. These sensors drive neural stimulation, which elicits sensations of knee motion and the sole of the foot touching the ground. We found that walking speed and self-reported confidence increased while mental and physical fatigue decreased for both participants during neural sensory feedback compared to the no stimulation trials. Furthermore, participants exhibited reduced phantom limb pain with neural sensory feedback. The results from these proof-of-concept cases provide the rationale for larger population studies investigating the clinical utility of neuroprostheses that restore sensory feedback.



Nat Med: 30 Aug 2019; 25:1356-1363
Petrini FM, Bumbasirevic M, Valle G, Ilic V, ... Micera S, Raspopovic S
Nat Med: 30 Aug 2019; 25:1356-1363 | PMID: 31501600
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Impact:
Abstract

Clinical lessons learned from the first leg of the CAR T cell journey.

Majzner RG, Mackall CL

Chimeric antigen receptor (CAR) T cell therapy for B cell malignancies has surpassed expectations, driving an ever-expanding number of clinical trials and the first US Food and Drug Administration approvals of cell therapies for the treatment of cancer. This experience has illuminated some generalizable requirements for CAR T cell efficacy as well as the interplay between disease biology and clinical outcomes. Major CAR intrinsic variables affecting T cell behavior have been defined, and mechanisms of tumor resistance are increasingly understood. Here, we review the clinical experience with CAR T cells amassed to date, including but not limited to B cell malignancies, emphasizing factors associated with efficacy, resistance and major barriers to success. We also discuss how these insights are driving next-generation clinical trials, including those in solid tumors.



Nat Med: 30 Aug 2019; 25:1341-1355
Majzner RG, Mackall CL
Nat Med: 30 Aug 2019; 25:1341-1355 | PMID: 31501612
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Impact:
Abstract

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

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

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



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

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

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

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



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

Adipose lipid turnover and long-term changes in body weight.

Arner P, Bernard S, Appelsved L, Fu KY, ... Rydén M, Spalding KL

The worldwide obesity epidemic makes it important to understand how lipid turnover (the capacity to store and remove lipids) regulates adipose tissue mass. Cross-sectional studies have shown that excess body fat is associated with decreased adipose lipid removal rates. Whether lipid turnover is constant over the life span or changes during long-term weight increase or loss is unknown. We determined the turnover of fat cell lipids in adults followed for up to 16 years, by measuring the incorporation of nuclear bomb test-derived C in adipose tissue triglycerides. Lipid removal rate decreases during aging, with a failure to reciprocally adjust the rate of lipid uptake resulting in weight gain. Substantial weight loss is not driven by changes in lipid removal but by the rate of lipid uptake in adipose tissue. Furthermore, individuals with a low baseline lipid removal rate are more likely to remain weight-stable after weight loss. Therefore, lipid turnover adaptation might be important for maintaining pronounced weight loss. Together these findings identify adipose lipid turnover as an important factor for the long-term development of overweight/obesity and weight loss maintenance in humans.



Nat Med: 30 Aug 2019; 25:1385-1389
Arner P, Bernard S, Appelsved L, Fu KY, ... Rydén M, Spalding KL
Nat Med: 30 Aug 2019; 25:1385-1389 | PMID: 31501613
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Impact:
Abstract

Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population.

Licher S, Ahmad S, Karamujić-Čomić H, Voortman T, ... Ikram MA, Ikram MK

The exact etiology of dementia is still unclear, but both genetic and lifestyle factors are thought to be key drivers of this complex disease. The recognition of familial patterns of dementia has led to the discovery of genetic factors that have a role in the pathogenesis of dementia, including the apolipoprotein E (APOE) genotype and a large and still-growing number of genetic variants. Beyond genetic architecture, several modifiable risk factors have been implicated in the development of dementia. Prevention trials of measures to halt or delay cognitive decline are increasingly recruiting older individuals who are genetically predisposed to dementia. However, it remains unclear whether targeted health and lifestyle interventions can attenuate or even offset increased genetic risk. Here, we leverage long-term data on both genetic and modifiable risk factors from 6,352 individuals aged 55 years and older in the population-based Rotterdam Study. In this study, we demonstrate that, in individuals at low and intermediate genetic risk, favorable modifiable-risk profiles are related to a lower risk of dementia compared to unfavorable profiles. In contrast, these protective associations were not found in those at high genetic risk.



Nat Med: 30 Aug 2019; 25:1364-1369
Licher S, Ahmad S, Karamujić-Čomić H, Voortman T, ... Ikram MA, Ikram MK
Nat Med: 30 Aug 2019; 25:1364-1369 | PMID: 31451782
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Impact:
Abstract

A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients.

Cassotta A, Mikol V, Bertrand T, Pouzieux S, ... Lanzavecchia A, Piccoli L

Natalizumab (NZM), a humanized monoclonal IgG4 antibody to α4 integrins, is used to treat patients with relapsing-remitting multiple sclerosis (MS), but in about 6% of the cases persistent neutralizing anti-drug antibodies (ADAs) are induced leading to therapy discontinuation. To understand the basis of the ADA response and the mechanism of ADA-mediated neutralization, we performed an in-depth analysis of the B and T cell responses in two patients. By characterizing a large panel of NZM-specific monoclonal antibodies, we found that, in both patients, the response was polyclonal and targeted different epitopes of the NZM idiotype. The neutralizing activity was acquired through somatic mutations and correlated with a slow dissociation rate, a finding that was supported by structural data. Interestingly, in both patients, the analysis of the CD4 T cell response, combined with mass spectrometry-based peptidomics, revealed a single immunodominant T cell epitope spanning the FR2-CDR2 region of the NZM light chain. Moreover, a CDR2-modified version of NZM was not recognized by T cells, while retaining binding to α4 integrins. Collectively, our integrated analysis identifies the basis of T-B collaboration that leads to ADA-mediated therapeutic resistance and delineates an approach to design novel deimmunized antibodies for autoimmune disease and cancer treatment.



Nat Med: 30 Aug 2019; 25:1402-1407
Cassotta A, Mikol V, Bertrand T, Pouzieux S, ... Lanzavecchia A, Piccoli L
Nat Med: 30 Aug 2019; 25:1402-1407 | PMID: 31501610
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Impact:
Abstract

Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity.

Yang H, Xia L, Chen J, Zhang S, ... Kroemer G, Ma Y

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.



Nat Med: 30 Aug 2019; 25:1428-1441
Yang H, Xia L, Chen J, Zhang S, ... Kroemer G, Ma Y
Nat Med: 30 Aug 2019; 25:1428-1441 | PMID: 31501614
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Impact:
Abstract

An augmented reality microscope with real-time artificial intelligence integration for cancer diagnosis.

Chen PC, Gadepalli K, MacDonald R, Liu Y, ... Mermel CH, Stumpe MC

The microscopic assessment of tissue samples is instrumental for the diagnosis and staging of cancer, and thus guides therapy. However, these assessments demonstrate considerable variability and many regions of the world lack access to trained pathologists. Though artificial intelligence (AI) promises to improve the access and quality of healthcare, the costs of image digitization in pathology and difficulties in deploying AI solutions remain as barriers to real-world use. Here we propose a cost-effective solution: the augmented reality microscope (ARM). The ARM overlays AI-based information onto the current view of the sample in real time, enabling seamless integration of AI into routine workflows. We demonstrate the utility of ARM in the detection of metastatic breast cancer and the identification of prostate cancer, with latency compatible with real-time use. We anticipate that the ARM will remove barriers towards the use of AI designed to improve the accuracy and efficiency of cancer diagnosis.



Nat Med: 30 Aug 2019; 25:1453-1457
Chen PC, Gadepalli K, MacDonald R, Liu Y, ... Mermel CH, Stumpe MC
Nat Med: 30 Aug 2019; 25:1453-1457 | PMID: 31406351
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Impact:
Abstract

Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma.

Kim JW, Marquez CP, Kostyrko K, Koehne AL, ... Cochran JR, Sweet-Cordero EA

Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.



Nat Med: 06 Nov 2019; epub ahead of print
Kim JW, Marquez CP, Kostyrko K, Koehne AL, ... Cochran JR, Sweet-Cordero EA
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700175
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Impact:
Abstract

Gut microbiome alteration in MORDOR I: a community-randomized trial of mass azithromycin distribution.

Doan T, Hinterwirth A, Worden L, Arzika AM, ... Keenan JD, Lietman TM

The MORDOR I trial, conducted in Niger, Malawi and Tanzania, demonstrated that mass azithromycin distribution to preschool children reduced childhood mortality. However, the large but simple trial design precluded determination of the mechanisms involved. Here we examined the gut microbiome of preschool children from 30 Nigerien communities randomized to either biannual azithromycin or placebo. Gut microbiome γ-diversity was not significantly altered (P = 0.08), but the relative abundances of two Campylobacter species, along with another 33 gut bacteria, were significantly reduced in children treated with azithromycin at the 24-month follow-up. Metagenomic analysis revealed functional differences in gut bacteria between treatment groups. Resistome analysis showed an increase in macrolide resistance gene expression in gut microbiota in communities treated with azithromycin (P = 0.004). These results suggest that prolonged mass azithromycin distribution to reduce childhood mortality reduces certain gut bacteria, including known pathogens, while selecting for antibiotic resistance.



Nat Med: 30 Aug 2019; 25:1370-1376
Doan T, Hinterwirth A, Worden L, Arzika AM, ... Keenan JD, Lietman TM
Nat Med: 30 Aug 2019; 25:1370-1376 | PMID: 31406349
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Abstract

Resistance to TRK inhibition mediated by convergent MAPK pathway activation.

Cocco E, Schram AM, Kulick A, Misale S, ... Drilon A, Scaltriti M

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition. With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors. Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design.



Nat Med: 30 Aug 2019; 25:1422-1427
Cocco E, Schram AM, Kulick A, Misale S, ... Drilon A, Scaltriti M
Nat Med: 30 Aug 2019; 25:1422-1427 | PMID: 31406350
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Abstract

A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model.

Yant SR, Mulato A, Hansen D, Tse WC, ... Cihlar T, Link JO

People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options. As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently. Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection.



Nat Med: 30 Aug 2019; 25:1377-1384
Yant SR, Mulato A, Hansen D, Tse WC, ... Cihlar T, Link JO
Nat Med: 30 Aug 2019; 25:1377-1384 | PMID: 31501601
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Impact:
Abstract

High-resolution mycobiota analysis reveals dynamic intestinal translocation preceding invasive candidiasis.

Zhai B, Ola M, Rolling T, Tosini NL, ... Taur Y, Hohl TM

The intestinal microbiota is a complex community of bacteria, archaea, viruses, protists and fungi. Although the composition of bacterial constituents has been linked to immune homeostasis and infectious susceptibility, the role of non-bacterial constituents and cross-kingdom microbial interactions in these processes is poorly understood. Fungi represent a major cause of infectious morbidity and mortality in immunocompromised individuals, although the relationship of intestinal fungi (that is, the mycobiota) with fungal bloodstream infections remains undefined. We integrated an optimized bioinformatics pipeline with high-resolution mycobiota sequencing and comparative genomic analyses of fecal and blood specimens from recipients of allogeneic hematopoietic cell transplant. Patients with Candida bloodstream infection experienced a prior marked intestinal expansion of pathogenic Candida species; this expansion consisted of a complex dynamic between multiple species and subspecies with a stochastic translocation pattern into the bloodstream. The intestinal expansion of pathogenic Candida spp. was associated with a substantial loss in bacterial burden and diversity, particularly in the anaerobes. Thus, simultaneous analysis of intestinal fungi and bacteria identifies dysbiosis states across kingdoms that may promote fungal translocation and facilitate invasive disease. These findings support microbiota-driven approaches to identify patients at risk of fungal bloodstream infections for pre-emptive therapeutic intervention.



Nat Med: 05 Jan 2020; epub ahead of print
Zhai B, Ola M, Rolling T, Tosini NL, ... Taur Y, Hohl TM
Nat Med: 05 Jan 2020; epub ahead of print | PMID: 31907459
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Impact:
Abstract

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

Yofe I, Dahan R, Amit I

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



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

Putting decisions under the microscope.

Obermeyer Z

Ziad Obermeyer is an acting associate professor at the University of California, Berkeley, and an emergency physician. His teaching and research focus on how algorithms can aid in human decision-making in health care. Previously, he taught at Harvard Medical School, where he received the Early Independence Award, the most prestigious award for early-career scientists given by the US National Institutes of Health.



Nat Med: 06 Nov 2019; epub ahead of print
Obermeyer Z
Nat Med: 06 Nov 2019; epub ahead of print | PMID: 31700167
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Impact:
Abstract

Plasma protein patterns as comprehensive indicators of health.

Williams SA, Kivimaki M, Langenberg C, Hingorani AD, ... Ganz P, Wareham NJ

Proteins are effector molecules that mediate the functions of genes and modulate comorbidities, behaviors and drug treatments. They represent an enormous potential resource for personalized, systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check.



Nat Med: 01 Dec 2019; epub ahead of print
Williams SA, Kivimaki M, Langenberg C, Hingorani AD, ... Ganz P, Wareham NJ
Nat Med: 01 Dec 2019; epub ahead of print | PMID: 31792462
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Impact:
Abstract

Do no harm: a roadmap for responsible machine learning for health care.

Wiens J, Saria S, Sendak M, Ghassemi M, ... Thadaney-Israni S, Goldenberg A

Interest in machine-learning applications within medicine has been growing, but few studies have progressed to deployment in patient care. We present a framework, context and ultimately guidelines for accelerating the translation of machine-learning-based interventions in health care. To be successful, translation will require a team of engaged stakeholders and a systematic process from beginning (problem formulation) to end (widespread deployment).



Nat Med: 30 Aug 2019; 25:1337-1340
Wiens J, Saria S, Sendak M, Ghassemi M, ... Thadaney-Israni S, Goldenberg A
Nat Med: 30 Aug 2019; 25:1337-1340 | PMID: 31427808
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Impact:
Abstract

Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR.

Ghorashian S, Kramer AM, Onuoha S, Wright G, ... Pule MA, Amrolia PJ

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL), but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40-60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19 clones. Some factors, including the choice of single-chain spacer and extracellular and costimulatory domains, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831 ), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.



Nat Med: 30 Aug 2019; 25:1408-1414
Ghorashian S, Kramer AM, Onuoha S, Wright G, ... Pule MA, Amrolia PJ
Nat Med: 30 Aug 2019; 25:1408-1414 | PMID: 31477906
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Impact:
Abstract

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

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

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



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

In vitro fertilization does not increase the incidence of de novo copy number alterations in fetal and placental lineages.

Zamani Esteki M, Viltrop T, TÅ¡uiko O, Tiirats A, ... Vermeesch JR, Salumets A

Although chromosomal instability (CIN) is a common phenomenon in cleavage-stage embryogenesis following in vitro fertilization (IVF), its rate in naturally conceived human embryos is unknown. CIN leads to mosaic embryos that contain a combination of genetically normal and abnormal cells, and is significantly higher in in vitro-produced preimplantation embryos as compared to in vivo-conceived preimplantation embryos. Even though embryos with CIN-derived complex aneuploidies may arrest between the cleavage and blastocyst stages of embryogenesis, a high number of embryos containing abnormal cells can pass this strong selection barrier. However, neither the prevalence nor extent of CIN during prenatal development and at birth, following IVF treatment, is well understood. Here we profiled the genomic landscape of fetal and placental tissues postpartum from both IVF and naturally conceived children, to investigate the prevalence and persistence of large genetic aberrations that probably arose from IVF-related CIN. We demonstrate that CIN is not preserved at later stages of prenatal development, and that de novo numerical aberrations or large structural DNA imbalances occur at similar rates in IVF and naturally conceived live-born neonates. Our findings affirm that human IVF treatment has no detrimental effect on the chromosomal constitution of fetal and placental lineages.



Nat Med: 03 Nov 2019; epub ahead of print
Zamani Esteki M, Viltrop T, TÅ¡uiko O, Tiirats A, ... Vermeesch JR, Salumets A
Nat Med: 03 Nov 2019; epub ahead of print | PMID: 31686035
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Impact:
Abstract

Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS.

Bravo-Hernandez M, Tadokoro T, Navarro MR, Platoshyn O, ... Cleveland DW, Marsala M

Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.



Nat Med: 22 Dec 2019; epub ahead of print
Bravo-Hernandez M, Tadokoro T, Navarro MR, Platoshyn O, ... Cleveland DW, Marsala M
Nat Med: 22 Dec 2019; epub ahead of print | PMID: 31873312
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Abstract

Resistance to autosomal dominant Alzheimer\'s disease in an APOE3 Christchurch homozygote: a case report.

Arboleda-Velasquez JF, Lopera F, O\'Hare M, Delgado-Tirado S, ... Reiman EM, Quiroz YT

We identified a PSEN1 (presenilin 1) mutation carrier from the world\'s largest autosomal dominant Alzheimer\'s disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer\'s disease.



Nat Med: 03 Nov 2019; epub ahead of print
Arboleda-Velasquez JF, Lopera F, O'Hare M, Delgado-Tirado S, ... Reiman EM, Quiroz YT
Nat Med: 03 Nov 2019; epub ahead of print | PMID: 31686034
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Impact:
Abstract

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

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

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



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

Near real-time intraoperative brain tumor diagnosis using stimulated Raman histology and deep neural networks.

Hollon TC, Pandian B, Adapa AR, Urias E, ... Camelo-Piragua S, Orringer DA

Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery. The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of processed tissue is time, resource and labor intensive. Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed, pathology workforce. In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH), a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20-30 min). In a multicenter, prospective clinical trial (n = 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, we implemented a semantic segmentation method to identify tumor-infiltrated diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.



Nat Med: 05 Jan 2020; epub ahead of print
Hollon TC, Pandian B, Adapa AR, Urias E, ... Camelo-Piragua S, Orringer DA
Nat Med: 05 Jan 2020; epub ahead of print | PMID: 31907460
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Impact:
Abstract

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

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

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



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

A case report of clonal EBV-like memory CD4 T cell activation in fatal checkpoint inhibitor-induced encephalitis.

Johnson DB, McDonnell WJ, Gonzalez-Ericsson PI, Al-Rohil RN, ... Sosman JA, Balko JM

Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4 T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45ROGZMBKi67) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4 and CD8 T cells as culprits of checkpoint inhibitor-associated immune encephalitis.



Nat Med: 30 Jul 2019; 25:1243-1250
Johnson DB, McDonnell WJ, Gonzalez-Ericsson PI, Al-Rohil RN, ... Sosman JA, Balko JM
Nat Med: 30 Jul 2019; 25:1243-1250 | PMID: 31332390
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Impact:
Abstract

Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma.

Goswami S, Walle T, Cornish AE, Basu S, ... Pe\'er D, Sharma P

Immune checkpoint therapy with anti-CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of many solid tumors. However, the clinical efficacy of immune checkpoint therapy is limited to a subset of patients with specific tumor types. Multiple clinical trials with combinatorial immune checkpoint strategies are ongoing; however, the mechanistic rationale for tumor-specific targeting of immune checkpoints is elusive. To garner an insight into tumor-specific immunomodulatory targets, we analyzed 94 patients representing five different cancer types, including those that respond relatively well to immune checkpoint therapy and those that do not, such as glioblastoma multiforme, prostate cancer and colorectal cancer. Through mass cytometry and single-cell RNA sequencing, we identified a unique population of CD73 macrophages in glioblastoma multiforme that persists after anti-PD-1 treatment. To test if targeting CD73 would be important for a successful combination strategy in glioblastoma multiforme, we performed reverse translational studies using CD73 mice. We found that the absence of CD73 improved survival in a murine model of glioblastoma multiforme treated with anti-CTLA-4 and anti-PD-1. Our data identified CD73 as a specific immunotherapeutic target to improve antitumor immune responses to immune checkpoint therapy in glioblastoma multiforme and demonstrate that comprehensive human and reverse translational studies can be used for rational design of combinatorial immune checkpoint strategies.



Nat Med: 22 Dec 2019; epub ahead of print
Goswami S, Walle T, Cornish AE, Basu S, ... Pe'er D, Sharma P
Nat Med: 22 Dec 2019; epub ahead of print | PMID: 31873309
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Impact:
Abstract

Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice.

Bárcena C, Valdés-Mas R, Mayoral P, Garabaya C, ... Quirós PM, López-Otín C

The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways. Gut microbiome deregulation has been implicated in major conditions such as obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease and cancer, but its precise role in aging remains to be elucidated. Here, we find that two different mouse models of progeria are characterized by intestinal dysbiosis with alterations that include an increase in the abundance of Proteobacteria and Cyanobacteria, and a decrease in the abundance of Verrucomicrobia. Consistent with these findings, we found that human progeria patients also display intestinal dysbiosis and that long-lived humans (that is, centenarians) exhibit a substantial increase in Verrucomicrobia and a reduction in Proteobacteria. Fecal microbiota transplantation from wild-type mice enhanced healthspan and lifespan in both progeroid mouse models, and transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial effects of reestablishing a healthy microbiome. Our results demonstrate that correction of the accelerated aging-associated intestinal dysbiosis is beneficial, suggesting the existence of a link between aging and the gut microbiota that provides a rationale for microbiome-based interventions against age-related diseases.



Nat Med: 30 Jul 2019; 25:1234-1242
Bárcena C, Valdés-Mas R, Mayoral P, Garabaya C, ... Quirós PM, López-Otín C
Nat Med: 30 Jul 2019; 25:1234-1242 | PMID: 31332389
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Impact:
Abstract

Autism risk in offspring can be assessed through quantification of male sperm mosaicism.

Breuss MW, Antaki D, George RD, Kleiber M, ... Sebat J, Gleeson JG

De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father\'s sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.



Nat Med: 22 Dec 2019; epub ahead of print
Breuss MW, Antaki D, George RD, Kleiber M, ... Sebat J, Gleeson JG
Nat Med: 22 Dec 2019; epub ahead of print | PMID: 31873310
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Impact:
Abstract

Metabolic perturbations and cellular stress underpin susceptibility to symptomatic live-attenuated yellow fever infection.

Chan KR, Gan ES, Chan CYY, Liang C, ... Low JG, Ooi EE

Flaviviral infections result in a wide spectrum of clinical outcomes, ranging from asymptomatic infection to severe disease. Although the correlates of severe disease have been explored, the pathophysiology that differentiates symptomatic from asymptomatic infection remains undefined. To understand the molecular underpinnings of symptomatic infection, the blood transcriptomic and metabolomic profiles of individuals were examined before and after inoculation with the live yellow fever viral vaccine (YF17D). It was found that individuals with adaptive endoplasmic reticulum (ER) stress and reduced tricarboxylic acid cycle activity at baseline showed increased susceptibility to symptomatic outcome. YF17D infection in these individuals induced maladaptive ER stress, triggering downstream proinflammatory responses that correlated with symptomatic outcome. The findings of the present study thus suggest that the ER stress response and immunometabolism underpin symptomatic yellow fever and possibly even other flaviviral infections. Modulating either ER stress or metabolism could be exploited for prophylaxis against symptomatic flaviviral infection outcome.



Nat Med: 30 Jul 2019; 25:1218-1224
Chan KR, Gan ES, Chan CYY, Liang C, ... Low JG, Ooi EE
Nat Med: 30 Jul 2019; 25:1218-1224 | PMID: 31308506
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Impact:
Abstract

Designing stem-cell-based dopamine cell replacement trials for Parkinson\'s disease.

Barker RA

Clinical studies of Parkinson\'s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO ( NCT01898390 ), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials.



Nat Med: 29 Jun 2019; 25:1045-1053
Barker RA
Nat Med: 29 Jun 2019; 25:1045-1053 | PMID: 31263283
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Impact:
Abstract

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

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

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



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

Clinical-grade computational pathology using weakly supervised deep learning on whole slide images.

Campanella G, Hanna MG, Geneslaw L, Miraflor A, ... Klimstra DS, Fuchs TJ

The development of decision support systems for pathology and their deployment in clinical practice have been hindered by the need for large manually annotated datasets. To overcome this problem, we present a multiple instance learning-based deep learning system that uses only the reported diagnoses as labels for training, thereby avoiding expensive and time-consuming pixel-wise manual annotations. We evaluated this framework at scale on a dataset of 44,732 whole slide images from 15,187 patients without any form of data curation. Tests on prostate cancer, basal cell carcinoma and breast cancer metastases to axillary lymph nodes resulted in areas under the curve above 0.98 for all cancer types. Its clinical application would allow pathologists to exclude 65-75% of slides while retaining 100% sensitivity. Our results show that this system has the ability to train accurate classification models at unprecedented scale, laying the foundation for the deployment of computational decision support systems in clinical practice.



Nat Med: 30 Jul 2019; 25:1301-1309
Campanella G, Hanna MG, Geneslaw L, Miraflor A, ... Klimstra DS, Fuchs TJ
Nat Med: 30 Jul 2019; 25:1301-1309 | PMID: 31308507
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Impact:
Abstract

Investigation of the role of typhoid toxin in acute typhoid fever in a human challenge model.

Gibani MM, Jones E, Barton A, Jin C, ... Galán J, Pollard AJ

Salmonella Typhi is a human host-restricted pathogen that is responsible for typhoid fever in approximately 10.9 million people annually. The typhoid toxin is postulated to have a central role in disease pathogenesis, the establishment of chronic infection and human host restriction. However, its precise role in typhoid disease in humans is not fully defined. We studied the role of typhoid toxin in acute infection using a randomized, double-blind S. Typhi human challenge model. Forty healthy volunteers were randomized (1:1) to oral challenge with 10 colony-forming units of wild-type or an isogenic typhoid toxin deletion mutant (TN) of S. Typhi. We observed no significant difference in the rate of typhoid infection (fever ≥38 °C for ≥12 h and/or S. Typhi bacteremia) between participants challenged with wild-type or TN S. Typhi (15 out of 21 (71%) versus 15 out of 19 (79%); P = 0.58). The duration of bacteremia was significantly longer in participants challenged with the TN strain compared with wild-type (47.6 hours (28.9-97.0) versus 30.3(3.6-49.4); P ≤ 0.001). The clinical syndrome was otherwise indistinguishable between wild-type and TN groups. These data suggest that the typhoid toxin is not required for infection and the development of early typhoid fever symptoms within the context of a human challenge model. Further clinical data are required to assess the role of typhoid toxin in severe disease or the establishment of bacterial carriage.



Nat Med: 29 Jun 2019; 25:1082-1088
Gibani MM, Jones E, Barton A, Jin C, ... Galán J, Pollard AJ
Nat Med: 29 Jun 2019; 25:1082-1088 | PMID: 31270506
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Impact:
Abstract

Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression.

Segovia C, San José-Enériz E, Munera-Maravilla E, Martínez-Fernández M, ... Prósper F, Paramio JM

Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances. Recent molecular characterization has defined new (epi)genetic drivers and potential targets for bladder cancer. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients. Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (Pten; Trp53; Rb1; Rbl1) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.



Nat Med: 29 Jun 2019; 25:1073-1081
Segovia C, San José-Enériz E, Munera-Maravilla E, Martínez-Fernández M, ... Prósper F, Paramio JM
Nat Med: 29 Jun 2019; 25:1073-1081 | PMID: 31270502
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Impact:
Abstract

Clonal replacement of tumor-specific T cells following PD-1 blockade.

Yost KE, Satpathy AT, Wells DK, Qi Y, ... Chang ALS, Chang HY

Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8CD39 T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8 T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.



Nat Med: 30 Jul 2019; 25:1251-1259
Yost KE, Satpathy AT, Wells DK, Qi Y, ... Chang ALS, Chang HY
Nat Med: 30 Jul 2019; 25:1251-1259 | PMID: 31359002
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Impact:
Abstract

Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis.

Wirka RC, Wagh D, Paik DT, Pjanic M, ... Kim JB, Quertermous T

In response to various stimuli, vascular smooth muscle cells (SMCs) can de-differentiate, proliferate and migrate in a process known as phenotypic modulation. However, the phenotype of modulated SMCs in vivo during atherosclerosis and the influence of this process on coronary artery disease (CAD) risk have not been clearly established. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomic phenotype of modulated SMCs in vivo in atherosclerotic lesions of both mouse and human arteries and found that these cells transform into unique fibroblast-like cells, termed \'fibromyocytes\', rather than into a classical macrophage phenotype. SMC-specific knockout of TCF21-a causal CAD gene-markedly inhibited SMC phenotypic modulation in mice, leading to the presence of fewer fibromyocytes within lesions as well as within the protective fibrous cap of the lesions. Moreover, TCF21 expression was strongly associated with SMC phenotypic modulation in diseased human coronary arteries, and higher levels of TCF21 expression were associated with decreased CAD risk in human CAD-relevant tissues. These results establish a protective role for both TCF21 and SMC phenotypic modulation in this disease.



Nat Med: 30 Jul 2019; 25:1280-1289
Wirka RC, Wagh D, Paik DT, Pjanic M, ... Kim JB, Quertermous T
Nat Med: 30 Jul 2019; 25:1280-1289 | PMID: 31359001
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Impact:
Abstract

Farm-like indoor microbiota in non-farm homes protects children from asthma development.

Kirjavainen PV, Karvonen AM, Adams RI, Täubel M, ... von Mutius E, Pekkanen J

Asthma prevalence has increased in epidemic proportions with urbanization, but growing up on traditional farms offers protection even today. The asthma-protective effect of farms appears to be associated with rich home dust microbiota, which could be used to model a health-promoting indoor microbiome. Here we show by modeling differences in house dust microbiota composition between farm and non-farm homes of Finnish birth cohorts that in children who grow up in non-farm homes, asthma risk decreases as the similarity of their home bacterial microbiota composition to that of farm homes increases. The protective microbiota had a low abundance of Streptococcaceae relative to outdoor-associated bacterial taxa. The protective effect was independent of richness and total bacterial load and was associated with reduced proinflammatory cytokine responses against bacterial cell wall components ex vivo. We were able to reproduce these findings in a study among rural German children and showed that children living in German non-farm homes with an indoor microbiota more similar to Finnish farm homes have decreased asthma risk. The indoor dust microbiota composition appears to be a definable, reproducible predictor of asthma risk and a potential modifiable target for asthma prevention.



Nat Med: 29 Jun 2019; 25:1089-1095
Kirjavainen PV, Karvonen AM, Adams RI, Täubel M, ... von Mutius E, Pekkanen J
Nat Med: 29 Jun 2019; 25:1089-1095 | PMID: 31209334
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Impact:
Abstract

Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.

Powles T, Kockx M, Rodriguez-Vida A, Duran I, ... Banchereau R, Castellano D

Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers. Biomarkers may facilitate identification of these responding tumors. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309 ). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.



Nat Med: 03 Nov 2019; epub ahead of print
Powles T, Kockx M, Rodriguez-Vida A, Duran I, ... Banchereau R, Castellano D
Nat Med: 03 Nov 2019; epub ahead of print | PMID: 31686036
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Impact:
Abstract

Multiscale reverse engineering of the human ocular surface.

Seo J, Byun WY, Alisafaei F, Georgescu A, ... Bunya VY, Huh D

Here we present a miniaturized analog of a blinking human eye to reverse engineer the complexity of the interface between the ocular system and the external environment. Our model comprises human cells and provides unique capabilities to replicate multiscale structural organization, biological phenotypes and dynamically regulated environmental homeostasis of the human ocular surface. Using this biomimetic system, we discovered new biological effects of blink-induced mechanical forces. Furthermore, we developed a specialized in vitro model of evaporative dry-eye disease for high-content drug screening. This work advances our ability to emulate how human physiological systems interface with the external world, and may contribute to the future development of novel screening platforms for biopharmaceutical and environmental applications.



Nat Med: 30 Jul 2019; 25:1310-1318
Seo J, Byun WY, Alisafaei F, Georgescu A, ... Bunya VY, Huh D
Nat Med: 30 Jul 2019; 25:1310-1318 | PMID: 31384041
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Impact:
Abstract

Personal clinical history predicts antibiotic resistance of urinary tract infections.

Yelin I, Snitser O, Novich G, Katz R, ... Shalev V, Kishony R

Antibiotic resistance is prevalent among the bacterial pathogens causing urinary tract infections. However, antimicrobial treatment is often prescribed \'empirically\', in the absence of antibiotic susceptibility testing, risking mismatched and therefore ineffective treatment. Here, linking a 10-year longitudinal data set of over 700,000 community-acquired urinary tract infections with over 5,000,000 individually resolved records of antibiotic purchases, we identify strong associations of antibiotic resistance with the demographics, records of past urine cultures and history of drug purchases of the patients. When combined together, these associations allow for machine-learning-based personalized drug-specific predictions of antibiotic resistance, thereby enabling drug-prescribing algorithms that match an antibiotic treatment recommendation to the expected resistance of each sample. Applying these algorithms retrospectively, over a 1-year test period, we find that they greatly reduce the risk of mismatched treatment compared with the current standard of care. The clinical application of such algorithms may help improve the effectiveness of antimicrobial treatments.



Nat Med: 29 Jun 2019; 25:1143-1152
Yelin I, Snitser O, Novich G, Katz R, ... Shalev V, Kishony R
Nat Med: 29 Jun 2019; 25:1143-1152 | PMID: 31273328
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Impact:
Abstract

Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors.

Cejas P, Drier Y, Dreijerink KMA, Brosens LAA, ... Bernstein BE, Shivdasani RA

Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered \'non-functional\'. As clinical behaviors vary widely and distant metastases are eventually lethal, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and β-cells. Transcription factors ARX and PDX1 specify these normal cells, respectively, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARXPDX1 tumors and, within this subtype, in cases with alternative lengthening of telomeres. These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course and can inform postoperative clinical decisions.



Nat Med: 30 Jul 2019; 25:1260-1265
Cejas P, Drier Y, Dreijerink KMA, Brosens LAA, ... Bernstein BE, Shivdasani RA
Nat Med: 30 Jul 2019; 25:1260-1265 | PMID: 31263286
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Impact:
Abstract

Genetic testing, insurance discrimination and medical research: what the United States can learn from peer countries.

Bélisle-Pipon JC, Vayena E, Green RC, Cohen IG

While genetic testing may be the gateway to the future of medicine, it also poses challenges for individuals, especially in terms of differentiated treatments on the basis of their genetic characteristics. The fear of unwanted disclosure to insurers and the possibility of genetic discrimination can hamper the recruitment of individuals for clinical research that involves genetic testing. Precision medicine initiatives, such as All of Us, are proliferating in the United States. In order to succeed, however, they must ensure that the millions of Americans recruited to share their genetic data are not penalized with regard to life, disability and long-term insurance coverage. In this Perspective, we discuss several initiatives adopted by countries around the world, such as the United Kingdom and France, that better balance the interests of insurers and research subjects, and explain how the United States might learn from them. We call for regulatory and industry leadership to come together to establish a voluntary moratorium on insurance pricing with the aim of protecting research participants.



Nat Med: 30 Jul 2019; 25:1198-1204
Bélisle-Pipon JC, Vayena E, Green RC, Cohen IG
Nat Med: 30 Jul 2019; 25:1198-1204 | PMID: 31388181
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Impact:
Abstract

Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants.

Gopalakrishna KP, Macadangdang BR, Rogers MB, Tometich JT, ... Morowitz MJ, Hand TW

Neonates are protected from colonizing bacteria by antibodies secreted into maternal milk. Necrotizing enterocolitis (NEC) is a disease of neonatal preterm infants with high morbidity and mortality that is associated with intestinal inflammation driven by the microbiota. The incidence of NEC is substantially lower in infants fed with maternal milk, although the mechanisms that underlie this benefit are not clear. Here we show that maternal immunoglobulin A (IgA) is an important factor for protection against NEC. Analysis of IgA binding to fecal bacteria from preterm infants indicated that maternal milk was the predominant source of IgA in the first month of life and that a relative decrease in IgA-bound bacteria is associated with the development of NEC. Sequencing of IgA-bound and unbound bacteria revealed that before the onset of disease, NEC was associated with increasing domination by Enterobacteriaceae in the IgA-unbound fraction of the microbiota. Furthermore, we confirmed that IgA is critical for preventing NEC in a mouse model, in which pups that are reared by IgA-deficient mothers are susceptible to disease despite exposure to maternal milk. Our findings show that maternal IgA shapes the host-microbiota relationship of preterm neonates and that IgA in maternal milk is a critical and necessary factor for the prevention of NEC.



Nat Med: 29 Jun 2019; 25:1110-1115
Gopalakrishna KP, Macadangdang BR, Rogers MB, Tometich JT, ... Morowitz MJ, Hand TW
Nat Med: 29 Jun 2019; 25:1110-1115 | PMID: 31209335
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Impact:
Abstract

Publisher Correction: Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

Voorwerk L, Slagter M, Horlings HM, Sikorska K, ... Blank CU, Kok M

In the version of this article originally published, there was an error in Fig. 3j. A label on the heatmap read \"TGF-α signaling via NF-κB\". It should have read \"TNF-α signaling via NF-κB\". The error has been corrected in the HTML and PDF versions of this article.



Nat Med: 29 Jun 2019; 25:1175
Voorwerk L, Slagter M, Horlings HM, Sikorska K, ... Blank CU, Kok M
Nat Med: 29 Jun 2019; 25:1175 | PMID: 31209337
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Impact:
Abstract

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

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

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



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

A fully human transgene switch to regulate therapeutic protein production by cooling sensation.

Bai P, Liu Y, Xue S, Hamri GC, ... Xie M, Fussenegger M

The ability to safely control transgene expression with simple synthetic gene switches is critical for effective gene- and cell-based therapies. In the present study, the signaling pathway controlled by human transient receptor potential (TRP) melastatin 8 (hTRPM8), a TRP channel family member, is harnessed to control transgene expression. Human TRPM8 signaling is stimulated by menthol, an innocuous, natural, cooling compound, or by exposure to a cool environment (15-18 °C). By functionally linking hTRPM8-induced signaling to a synthetic promoter containing elements that bind nuclear factor of activated T cells, a synthetic gene circuit was designed that can be adjusted by exposure to either a cool environment or menthol. It was shown that this gene switch is functional in various cell types and human primary cells, as well as in mice implanted with engineered cells. In response to transdermal delivery of menthol, microencapsulated cell implants harboring this gene circuit, coupled to expression of either of two therapeutic proteins, insulin or a modified, activin type IIB, receptor ligand trap protein (mActRIIB-hFc), could alleviate hyperglycemia in alloxan-treated mice (a model of type 1 diabetes) or reverse muscle atrophy in dexamethasone-treated mice (a model of muscle wasting), respectively. This fully human-derived orthogonal transgene switch should be amenable to a wide range of clinical applications.



Nat Med: 30 Jul 2019; 25:1266-1273
Bai P, Liu Y, Xue S, Hamri GC, ... Xie M, Fussenegger M
Nat Med: 30 Jul 2019; 25:1266-1273 | PMID: 31285633
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Impact:
Abstract

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

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

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



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

GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis.

Galli E, Hartmann FJ, Schreiner B, Ingelfinger F, ... Olsson T, Becher B

Cytokine dysregulation is a central driver of chronic inflammatory diseases such as multiple sclerosis (MS). Here, we sought to determine the characteristic cellular and cytokine polarization profile in patients with relapsing-remitting multiple sclerosis (RRMS) by high-dimensional single-cell mass cytometry (CyTOF). Using a combination of neural network-based representation learning algorithms, we identified an expanded T helper cell subset in patients with MS, characterized by the expression of granulocyte-macrophage colony-stimulating factor and the C-X-C chemokine receptor type 4. This cellular signature, which includes expression of very late antigen 4 in peripheral blood, was also enriched in the central nervous system of patients with relapsing-remitting multiple sclerosis. In independent validation cohorts, we confirmed that this cell population is increased in patients with MS compared with other inflammatory and non-inflammatory conditions. Lastly, we also found the population to be reduced under effective disease-modifying therapy, suggesting that the identified T cell profile represents a specific therapeutic target in MS.



Nat Med: 30 Jul 2019; 25:1290-1300
Galli E, Hartmann FJ, Schreiner B, Ingelfinger F, ... Olsson T, Becher B
Nat Med: 30 Jul 2019; 25:1290-1300 | PMID: 31332391
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Impact:
Abstract

Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children.

Nielsen-Saines K, Brasil P, Kerin T, Vasconcelos Z, ... Cheng G, Moreira ME

We report neurodevelopmental outcomes in 216 infants followed since the time of PCR-confirmed maternal Zika virus (ZIKV) infection in pregnancy during the Rio de Janeiro epidemic of 2015-2016 (refs. ). Neurodevelopment was assessed by Bayley Scales of Infant and Toddler Development, third edition (Bayley-III; cognitive, language and motor domains) in 146 children and through neurodevelopment questionnaires/neurological examinations in 70 remaining children. Complete eye exams (n = 137) and hearing assessments (n = 114) were also performed. Below-average neurodevelopment and/or abnormal eye or hearing assessments were noted in 31.5% of children between 7 and 32 months of age. Among children assessed by Bayley-III, 12% scored below -2 s.d. (score <70; a score of 100 ± 2 s.d. is the range) in at least one domain; and 28% scored between -1 and -2 s.d. in any domain (scores <85-70). Language function was most affected, with 35% of 146 children below average. Improved neurodevelopmental outcomes were noted in female children, term babies, children with normal eye exams and maternal infection later in pregnancy (P = 0.01). We noted resolution of microcephaly with normal neurodevelopment in two of eight children, development of secondary microcephaly in two other children and autism spectrum disorder in three previously healthy children in the second year of life.



Nat Med: 30 Jul 2019; 25:1213-1217
Nielsen-Saines K, Brasil P, Kerin T, Vasconcelos Z, ... Cheng G, Moreira ME
Nat Med: 30 Jul 2019; 25:1213-1217 | PMID: 31285631
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Impact:
Abstract

Mapping exclusive breastfeeding in Africa between 2000 and 2017.

Bhattacharjee NV, Schaeffer LE, Marczak LB, Ross JM, ... Dwyer-Lindgren L, Hay SI

Exclusive breastfeeding (EBF)-giving infants only breast-milk (and medications, oral rehydration salts and vitamins as needed) with no additional food or drink for their first six months of life-is one of the most effective strategies for preventing child mortality. Despite these advantages, only 37% of infants under 6 months of age in Africa were exclusively breastfed in 2017, and the practice of EBF varies by population. Here, we present a fine-scale geospatial analysis of EBF prevalence and trends in 49 African countries from 2000-2017, providing policy-relevant administrative- and national-level estimates. Previous national-level analyses found that most countries will not meet the World Health Organization\'s Global Nutrition Target of 50% EBF prevalence by 2025. Our analyses show that even fewer will achieve this ambition in all subnational areas. Our estimates provide the ability to visualize subnational EBF variability and identify populations in need of additional breastfeeding support.



Nat Med: 30 Jul 2019; 25:1205-1212
Bhattacharjee NV, Schaeffer LE, Marczak LB, Ross JM, ... Dwyer-Lindgren L, Hay SI
Nat Med: 30 Jul 2019; 25:1205-1212 | PMID: 31332393
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Abstract

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

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

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



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

Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.

Liu D, Schilling B, Liu D, Sucker A, ... Van Allen EM, Schadendorf D

Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.



Nat Med: 01 Dec 2019; epub ahead of print
Liu D, Schilling B, Liu D, Sucker A, ... Van Allen EM, Schadendorf D
Nat Med: 01 Dec 2019; epub ahead of print | PMID: 31792460
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Abstract

Genome-wide association study of peripheral artery disease in the Million Veteran Program.

Klarin D, Lynch J, Aragam K, Chaffin M, ... Tsao PS, Damrauer SM

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.



Nat Med: 30 Jul 2019; 25:1274-1279
Klarin D, Lynch J, Aragam K, Chaffin M, ... Tsao PS, Damrauer SM
Nat Med: 30 Jul 2019; 25:1274-1279 | PMID: 31285632
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