Publications by authors named "Dan L Longo"

190 Publications

A Possible Role for Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination.

N Engl J Med 2021 Nov 24. Epub 2021 Nov 24.

From the Departments of Dermatology and Internal Medicine, Division of Hematology and Oncology, University of California, Davis, Sacramento (W.J.M.).

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http://dx.doi.org/10.1056/NEJMcibr2113694DOI Listing
November 2021

Increased efficacy of dual pro-inflammatory cytokine blockade on acute GVHD while maintaining GVT effects.

Blood 2021 Aug 23. Epub 2021 Aug 23.

University of California, Davis, Sacramento, California, United States.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potential curative option for treating a variety of hematologic diseases, but acute and chronic graft-versus-host disease (GVHD) remain major barriers limiting efficacy. Acute gut GVHD occurs with marked increases in pro-inflammatory cytokines (including TNF and IL-6), which we recently demonstrated was exacerbated in obesity resulting in severe gastrointestinal pathology. Given the pleiotropic and overlapping effects of these two cytokines, we assessed the impact of dual TNF and IL-6R blockade on GVHD as well as graft-versus tumor (GVT) effects in different mouse GVHD models. Early administration of combined blockade resulted in greater protection and survival from acute gut GVHD compared to single blockade regimens and even development of later chronic skin GVHD. Importantly, double cytokine blockade preserved GVT effects reinforcing that GVT and GVHD can be delineated and may result in greater efficacy in allo-HSCT.
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http://dx.doi.org/10.1182/blood.2021011216DOI Listing
August 2021

Obesity induces gut microbiota alterations and augments acute graft-versus-host disease after allogeneic stem cell transplantation.

Sci Transl Med 2020 11;12(571)

Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.

The efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by acute and chronic graft-versus-host disease (GVHD). The impact of obesity on allo-HSCT outcomes is poorly understood. Here, we report that obesity had a negative and selective impact on acute gut GVHD after allo-HSCT in mice with diet-induced obesity (DIO). These animals exhibited increased gut permeability, endotoxin translocation across the gut, and radiation-induced gastrointestinal damage after allo-HSCT. After allo-HSCT, both male and female DIO mouse recipients showed increased proinflammatory cytokine production and expression of the GVHD marker ST2 (IL-33R) and MHC class II molecules; they also exhibited decreased survival associated with acute severe gut GVHD. This rapid-onset, obesity-associated gut GVHD depended on donor CD4 T cells and occurred even with a minor MHC mismatch between donor and recipient animals. Retrospective analysis of clinical cohorts receiving allo-HSCT transplants from unrelated donors revealed that recipients with a high body mass index (BMI, >30) had reduced survival and higher serum ST2 concentrations compared with nonobese transplant recipients. Assessment of both DIO mice and allo-HSCT recipients with a high BMI revealed reduced gut microbiota diversity and decreased Clostridiaceae abundance. Prophylactic antibiotic treatment protected DIO mouse recipients from endotoxin translocation across the gut and increased inflammatory cytokine production, as well as gut pathology and mortality, but did not protect against later development of chronic skin GVHD. These results suggest that obesity-induced alterations of the gut microbiota may affect GVHD after allo-HSCT in DIO mice, which could be ameliorated by prophylactic antibiotic treatment.
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http://dx.doi.org/10.1126/scitranslmed.aay7713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525601PMC
November 2020

Minimal PD-1 expression in mouse and human NK cells under diverse conditions.

J Clin Invest 2020 06;130(6):3051-3068

Department of Dermatology, UCD, Sacramento, California, USA.

PD-1 expression is a hallmark of both early antigen-specific T cell activation and later chronic stimulation, suggesting key roles in both naive T cell priming and memory T cell responses. Although significant similarities exist between T cells and NK cells, there are critical differences in their biology and functions reflecting their respective adaptive and innate immune effector functions. Expression of PD-1 on NK cells is controversial despite rapid incorporation into clinical cancer trials. Our objective was to stringently and comprehensively assess expression of PD-1 on both mouse and human NK cells under multiple conditions and using a variety of readouts. We evaluated NK cells from primary human tumor samples, after ex vivo culturing, and from multiple mouse tumor and viral models using flow cytometry, quantitative reverse-transcriptase PCR (qRT-PCR), and RNA-Seq for PD-1 expression. We demonstrate that, under multiple conditions, human and mouse NK cells consistently lack PD-1 expression despite the marked upregulation of other activation/regulatory markers, such as TIGIT. This was in marked contrast to T cells, which were far more prominent within all tumors and expressed PD-1. These data have important implications when attempting to discern NK from T cell effects and to determine whether PD-1 targeting can be expected to have direct effects on NK cell functions.
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http://dx.doi.org/10.1172/JCI133353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260004PMC
June 2020

Personalized Medicine for Primary Treatment of Serous Ovarian Cancer.

Authors:
Dan L Longo

N Engl J Med 2019 12;381(25):2471-2474

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http://dx.doi.org/10.1056/NEJMe1914488DOI Listing
December 2019

Detecting Breast Cancer in Women with Dense Breasts.

Authors:
Dan L Longo

N Engl J Med 2019 11;381(22):2169-2170

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http://dx.doi.org/10.1056/NEJMe1912943DOI Listing
November 2019

Talking about Toxicity - "What We've Got Here Is a Failure to Communicate".

N Engl J Med 2019 Oct;381(15):1406-1408

From Massachusetts General Hospital, Boston (C.A.S.).

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http://dx.doi.org/10.1056/NEJMp1908310DOI Listing
October 2019

The Precision of Evidence Needed to Practice "Precision Medicine".

N Engl J Med 2019 06 3;380(25):2472-2474. Epub 2019 Jun 3.

From the Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom (D.J.H.).

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http://dx.doi.org/10.1056/NEJMe1906088DOI Listing
June 2019

The Surprisingly Positive Association Between Obesity and Cancer Immunotherapy Efficacy.

JAMA 2019 Apr;321(13):1247-1248

Department of Medicine, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jama.2019.0463DOI Listing
April 2019

Progress in BRCA-Mutated Ovarian Cancer.

N Engl J Med 2018 12;379(26):2567-2568

From the Departments of Hematology-Oncology and Medicine, Harvard Medical School (D.R.S.).

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http://dx.doi.org/10.1056/NEJMe1812644DOI Listing
December 2018

Plateletpheresis-associated lymphopenia in frequent platelet donors.

Blood 2019 02 14;133(6):605-614. Epub 2018 Nov 14.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

More than 1 million apheresis platelet collections are performed annually in the United States. After 2 healthy plateletpheresis donors were incidentally found to have low CD4 T-lymphocyte counts, we investigated whether plateletpheresis causes lymphopenia. We conducted a cross-sectional single-center study of platelet donors undergoing plateletpheresis with the Trima Accel, which removes leukocytes continuously with its leukoreduction system chamber. We recruited 3 groups of platelet donors based on the total number of plateletpheresis sessions in the prior 365 days: 1 or 2, 3 to 19, or 20 to 24. CD4 T-lymphocyte counts were <200 cells per microliter in 0/20, 2/20, and 6/20 donors, respectively ( = .019), and CD8 T-lymphocyte counts were low in 0/20, 4/20, and 11/20 donors, respectively ( < .001). The leukoreduction system chamber's lymphocyte-extraction efficiency was ∼15% to 20% for all groups. Immunophenotyping showed decreases in naive CD4 T-lymphocyte and T helper 17 (Th17) cell percentages, increases in CD4 and CD8 effector memory, Th1, and regulatory T cell percentages, and stable naive CD8 and Th2 percentages across groups. T-cell receptor repertoire analyses showed similar clonal diversity in all groups. Donor screening questionnaires supported the good health of the donors, who tested negative at each donation for multiple pathogens, including HIV. Frequent plateletpheresis utilizing a leukoreduction system chamber is associated with CD4 and CD8 T-cell lymphopenia in healthy platelet donors. The mechanism may be repeated extraction of these cells during plateletpheresis. The cytopenias do not appear to be harmful.
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http://dx.doi.org/10.1182/blood-2018-09-873125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367645PMC
February 2019

Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade.

Nat Med 2019 01 12;25(1):141-151. Epub 2018 Nov 12.

Masonic Cancer Center and Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.

The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.
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http://dx.doi.org/10.1038/s41591-018-0221-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324991PMC
January 2019

Macrophage Checkpoint Blockade in Cancer - Back to the Future.

N Engl J Med 2018 11;379(18):1777-1779

From the Humanitas Clinical and Research Center and Humanitas University, Milan (A.M.); and the William Harvey Research Institute, Queen Mary University of London, London (A.M.).

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http://dx.doi.org/10.1056/NEJMe1811699DOI Listing
November 2018

Exploiting Viruses to Treat Diseases.

N Engl J Med 2018 07 26;379(2):194-196. Epub 2018 Jun 26.

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http://dx.doi.org/10.1056/NEJMe1807181DOI Listing
July 2018

Recent progress in systemic treatment for lung cancer.

Curr Opin Pulm Med 2018 07;24(4):355-366

Harvard Medical School, Brigham and Women's Hospital, Dana Farber Cancer Institute, Boston, Massachusetts, USA.

Purpose Of Review: We intend to highlight progress made in 2017 to lung cancer molecular nosology and application of new knowledge to treatment.

Recent Findings: Studies have shown that agents targeting specific molecular defects in lung cancers such as epidermal growth factor receptor(egfr) mutations, alk or ros1 gene rearrangements, are more effective than conventional combination chemotherapy as primary treatment for various lung cancer subgroups. Identification of mechanisms of drug resistance has guided development of improved agents and effective salvage regimens. Progress in reversing tumor-induced immunosuppression has led to further improvements in response rates (RR) including some patients with prolonged durable remissions.

Summary: State-of-the-art management of patients with lung cancer requires information derived from tumor molecular analysis, obtained either directly from the tumor or from tumor-derived circulating DNA. Empiric combination chemotherapy is no longer uniformly the best available treatment for all patients. Therapeutic decisions should be guided by an understanding of molecular features of an individual patient's tumor. The future gains will likely emerge from finding optimal ways of combining targeted therapy, immunotherapy, and chemotherapy.
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http://dx.doi.org/10.1097/MCP.0000000000000493DOI Listing
July 2018

A Milestone for CAR T Cells.

N Engl J Med 2017 12 10;377(26):2593-2596. Epub 2017 Dec 10.

From the Earle A. Chiles Research Institute and the Providence Portland Medical Center, Portland, OR (E.T., W.J.U.).

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http://dx.doi.org/10.1056/NEJMe1714680DOI Listing
December 2017

Progress in the Treatment of Hodgkin's Lymphoma.

N Engl J Med 2018 Jan 10;378(4):392-394. Epub 2017 Dec 10.

From the Yale Cancer Center, New Haven, CT (V.T.D.).

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http://dx.doi.org/10.1056/NEJMe1715141DOI Listing
January 2018

Which Anti-CD20 Antibody Is Better in Follicular Lymphoma?

N Engl J Med 2017 10;377(14):1389-1390

From the University of Nebraska, Omaha (J.O.A.).

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http://dx.doi.org/10.1056/NEJMe1706154DOI Listing
October 2017

Licensing delineates helper and effector NK cell subsets during viral infection.

JCI Insight 2017 May 18;2(10). Epub 2017 May 18.

Department of Dermatology.

Natural killer (NK) cells can be divided into phenotypic subsets based on expression of receptors that bind self-MHC-I molecules, a concept termed licensing or education. Here we show NK cell subsets with different migratory, effector, and immunoregulatory functions in dendritic cell and antigen (ag)-specific CD8+ T cell responses during influenza and murine cytomegalovirus infections. Shortly after infection, unlicensed NK cells localized in draining lymph nodes and produced GM-CSF, which correlated with the expansion and activation of dendritic cells, and resulted in greater and sustained ag-specific T cell responses. In contrast, licensed NK cells preferentially migrated to infected tissues and produced IFN-γ. Importantly, human NK cell subsets exhibited similar phenotypic characteristics. Collectively, our studies demonstrate a critical demarcation between the functions of licensed and unlicensed NK cell subsets, with the former functioning as the classical effector subset and the latter as the stimulator of adaptive immunity helping to prime immune responses.
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http://dx.doi.org/10.1172/jci.insight.87032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436543PMC
May 2017

Imatinib Changed Everything.

Authors:
Dan L Longo

N Engl J Med 2017 03;376(10):982-983

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http://dx.doi.org/10.1056/NEJMe1700833DOI Listing
March 2017

Novel genetic loci associated with hippocampal volume.

Nat Commun 2017 01 18;8:13624. Epub 2017 Jan 18.

Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA.

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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http://dx.doi.org/10.1038/ncomms13624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253632PMC
January 2017

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis.

Am J Hum Genet 2017 Jan 22;100(1):51-63. Epub 2016 Dec 22.

Icahn Institute for Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.
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http://dx.doi.org/10.1016/j.ajhg.2016.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223059PMC
January 2017

PARP Inhibitors in Ovarian Cancer Treatment.

N Engl J Med 2016 12;375(22):2197-2198

From the Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York (D.R.S.).

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http://dx.doi.org/10.1056/NEJMe1612843DOI Listing
December 2016

Novel genetic loci underlying human intracranial volume identified through genome-wide association.

Nat Neurosci 2016 12 3;19(12):1569-1582. Epub 2016 Oct 3.

Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht, the Netherlands.

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
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http://dx.doi.org/10.1038/nn.4398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227112PMC
December 2016

Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.

Cell Metab 2016 06;23(6):1093-1112

Laboratory of Molecular Gerontology, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.

Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.
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http://dx.doi.org/10.1016/j.cmet.2016.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911707PMC
June 2016

More on Data Sharing.

N Engl J Med 2016 05;374(19):1896-7

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http://dx.doi.org/10.1056/NEJMc1602586DOI Listing
May 2016
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