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  • Arrhythmogenic Right Ventricular Cardiomyopathy: Progress Toward Personalized Management
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Cynthia A. James, Hugh Calkins

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by fibrofatty replacement of the ventricular myocardium, a high risk of ventricular arrhythmias, and progressive ventricular dysfunction. The clinical course is highly variable, and optimal approaches to management remain undefined. ARVC is associated with pathogenic variants in genes encoding the cardiac desmosome. Genetic testing facilitates identification of at-risk family members, but penetrance of ARVC in pathogenic variant carriers is difficult to predict. Participation in endurance exercise is a known key risk factor. However, there remains significant uncertainty about which family member will develop disease and how best to approach longitudinal screening. Our clinically focused review describes how new insights gained from natural history studies, improved understanding of pathogenic mechanisms, and appreciation of genetic and environmental modifiers have set the stage for developing personalized approaches to managing both ARVC patients and their at-risk family members.

    更新日期:2019-11-18
  • Capitalizing on Insights from Human Genetics to Identify Novel Therapeutic Targets for Coronary Artery Disease
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Erica P. Young, Nathan O. Stitziel

    Coronary artery disease (CAD) is a major cause of morbidity and mortality. Unfortunately, despite decades of research focused on disease pathogenesis, we still lack a sufficient pharmacopeia for preventing CAD. The failure of many novel cardiovascular drugs to improve clinical outcomes reflects the major substantial challenge of drug development: identifying causal mechanisms that can be therapeutically manipulated to lower disease risk. Identifying genetic variants that are associated with risk of CAD has emerged as a clear path toward improving our understanding of the underlying mechanisms that lead to disease and to the development of new therapies. Here, we review the potential utility and limitations of using human genetics to guide the identification of therapeutic targets for CAD.

    更新日期:2019-11-18
  • Innovations in Ventricular Assist Devices for End-Stage Heart Failure
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Robert J.H. Miller, Jeffrey J. Teuteberg, Sharon A. Hunt

    The number of patients with end-stage heart failure (HF) continues to increase over time, but there has been little change in the availability of organs for cardiac transplantation, intensifying the demand for left ventricular assist devices (LVADs) as a bridge to transplantation. There is also a growing number of patients with end-stage HF who are not transplant candidates but may be eligible for long-term support with an LVAD, known as destination therapy. Due to this increasing demand, LVAD technology has evolved, resulting in transformative improvements in outcomes. Additionally, with growing clinical experience patient management continues to be refined, leading to iterative improvements in outcomes. With outcomes continuing to improve, the potential benefit from LVAD therapy is being considered for patients earlier in their course of advanced HF. We review recent changes in technology, patient management, and implant decision making in LVAD therapy.

    更新日期:2019-11-18
  • New and Emerging Therapies for Pulmonary Arterial Hypertension
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Edda Spiekerkoetter, Steven M. Kawut, Vinicio A. de Jesus Perez

    Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that causes right ventricular dysfunction and exercise limitation and progresses to death. New findings from translational studies have suggested alternative pathways for treatment. These avenues include sex hormones, genetic abnormalities and DNA damage, elastase inhibition, metabolic dysfunction, cellular therapies, and anti-inflammatory approaches. Both novel and repurposed compounds with rationale from preclinical experimental models and human cells are now in clinical trials in patients with PAH. Findings from these studies will elucidate the pathobiology of PAH and may result in clinically important improvements in outcome.

    更新日期:2019-11-18
  • Non–Vitamin K Antagonist Oral Anticoagulants in the Treatment of Atrial Fibrillation
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Alexander C. Fanaroff, E. Magnus Ohman

    Atrial fibrillation (AF) increases a patient's stroke risk four- to five-fold. Anticoagulation with the vitamin K antagonist (VKA) warfarin reduces the risk of stroke by 67%, but warfarin carries a significant risk of major bleeding and has unpredictable pharmacodynamics with a narrow therapeutic window, necessitating frequent monitoring of its anticoagulant effect. The non–vitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban provide more predictable anticoagulant activity than warfarin with a lower risk of major bleeding, and each is noninferior to warfarin for the prevention of stroke. All have earned regulatory approval in the past eight years. At least one of the NOACs is approved for use in all patients with AF, except those with mechanical valves and rheumatic mitral valve disease, for whom warfarin remains the only option. Recent clinical trials have shown that antithrombotic regimens including NOACs are safe and effective in patients with AF who need potent antiplatelet therapy.

    更新日期:2019-11-18
  • Molecular Diagnostics for Mycobacterium tuberculosis Infection
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Kristen V. Dicks, Jason E. Stout

    Resistance to antimycobacterial drugs is a major barrier to effective treatment of Mycobacterium tuberculosis infection. Molecular diagnostic techniques based on the association between specific gene mutations and phenotypic resistance to certain drugs offer the opportunity to rapidly ascertain whether drug resistance is present and to alter treatment before further resistance develops. Current barriers to successful implementation of rapid diagnostics include imperfect knowledge regarding the full spectrum of mutations associated with resistance, limited utilization of molecular diagnostics where they are most needed, and the requirement for specialized laboratory facilities to perform molecular testing. Further understanding of genotypic–phenotypic correlates of resistance and streamlined implementation platforms will be necessary to optimize the public health impact of molecular resistance testing for M. tuberculosis.

    更新日期:2019-11-18
  • Structure-Based Vaccine Antigen Design
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Barney S. Graham, Morgan S.A. Gilman, Jason S. McLellan

    Enabled by new approaches for rapid identification and selection of human monoclonal antibodies, atomic-level structural information for viral surface proteins, and capacity for precision engineering of protein immunogens and self-assembling nanoparticles, a new era of antigen design and display options has evolved. While HIV-1 vaccine development has been a driving force behind these technologies and concepts, clinical proof-of-concept for structure-based vaccine design may first be achieved for respiratory syncytial virus (RSV), where conformation-dependent access to neutralization-sensitive epitopes on the fusion glycoprotein determines the capacity to induce potent neutralizing activity. Success with RSV has motivated structure-based stabilization of other class I viral fusion proteins for use as immunogens and demonstrated the importance of structural information for developing vaccines against other viral pathogens, particularly difficult targets that have resisted prior vaccine development efforts. Solving viral surface protein structures also supports rapid vaccine antigen design and application of platform manufacturing approaches for emerging pathogens.

    更新日期:2019-11-18
  • The Global Landscape of Tuberculosis Therapeutics
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Jeffrey A. Tornheim, Kelly E. Dooley

    Tuberculosis (TB) is one of the oldest infections afflicting humans yet remains the number one infectious disease killer worldwide. Despite decades of experience treating this disease, TB regimens require months of multidrug therapy, even for latent infections. There have been important recent advances in treatment options across the spectrum of TB, from latent infection to extensively drug-resistant (XDR) TB disease. In addition, new, potent drugs are emerging out of the development pipeline and are being tested in novel regimens in multiple currently enrolling trials. Shorter, safer regimens for many forms of TB are now available or are in our near-term vision. We review recent advances in TB therapeutics and provide an overview of the upcoming clinical trials landscape that will help define the future of worldwide TB treatment.

    更新日期:2019-11-18
  • Zika Virus Vaccine Development: Progress in the Face of New Challenges
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Michael S. Diamond, Julie E. Ledgerwood, Theodore C. Pierson

    Zika virus (ZIKV) emerged at a global level when it spread to the Americas and began causing congenital malformations and microcephaly in 2015. A rapid response by academia, government, public health infrastructure, and industry has enabled the expedited development and testing of a suite of vaccine platforms aiming to control and eliminate ZIKV-induced disease. Analysis of key immunization and pathogenesis studies in multiple animal models, including during pregnancy, has begun to define immune correlates of protection. Nonetheless, the deployment of ZIKV vaccines, along with the confirmation of their safety and efficacy, still has major challenges, one of which is related to the waning of the epidemic. In this review, we discuss the measures that enabled rapid progress and highlight the path forward for successful deployment of ZIKV vaccines.

    更新日期:2019-11-18
  • Long-Acting HIV Drugs for Treatment and Prevention
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Roy M. Gulick, Charles Flexner

    Antiretroviral drugs have revolutionized the treatment and prevention of HIV infection; however, adherence is critical for sustained efficacy. Current HIV treatment consists of three-drug regimens, and current HIV pre-exposure prophylaxis (PrEP) consists of a two-drug regimen; both generally require adherence to once-daily dosing. Long-acting formulations are useful in the treatment and prevention of other conditions (e.g., contraceptives, antipsychotics) and help promote adherence. Newer long-acting formulations of approved and investigational antiretroviral drugs in existing and newer mechanistic classes are under study for HIV treatment and prevention, including some phase III trials. Although long-acting antiretroviral drugs hold promise, some clinical challenges exist, including managing side effects, drug-drug interactions, pregnancy, and long-lasting drug concentrations that could lead to the development of drug resistance. This review aims to summarize currently available information on long-acting antiretroviral drugs for HIV treatment and prevention.

    更新日期:2019-11-18
  • DNA Methylation and Susceptibility to Autism Spectrum Disorder
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Martine W. Tremblay, Yong-hui Jiang

    The prevalence of autism spectrum disorder (ASD) has been increasing steadily over the last 20 years; however, the molecular basis for the majority of ASD cases remains unknown. Recent advances in next-generation sequencing and detection of DNA modifications have made methylation-dependent regulation of transcription an attractive hypothesis for being a causative factor in ASD etiology. Evidence for abnormal DNA methylation in ASD can be seen on multiple levels, from genetic mutations in epigenetic machinery to loci-specific and genome-wide changes in DNA methylation. Epimutations in DNA methylation can be acquired throughout life, as global DNA methylation reprogramming is dynamic during embryonic development and the early postnatal period that corresponds to the peak time of synaptogenesis. However, technical advances and causative evidence still need to be established before abnormal DNA methylation and ASD can be confidently associated.

    更新日期:2019-11-18
  • Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Ilse Gantois, Jelena Popic, Arkady Khoutorsky, Nahum Sonenberg

    Fragile X syndrome (FXS) is the most frequent inherited form of intellectual disability and autism spectrum disorder. Loss of the fragile X mental retardation protein, FMRP, engenders molecular, behavioral, and cognitive deficits in FXS patients. Experiments using different animal models advanced our knowledge of the pathophysiology of FXS and led to the discovery of many targets for drug treatments. In this review, we discuss the potential of metformin, an antidiabetic drug approved by the US Food and Drug Administration, to correct core symptoms of FXS and other neurological disorders in humans. We summarize its mechanisms of action in different animal and cellular models and human diseases.

    更新日期:2019-11-18
  • Postpartum Depression: Pathophysiology, Treatment, and Emerging Therapeutics
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Donna E. Stewart, Simone N. Vigod

    Postpartum depression (PPD) is common, disabling, and treatable. The strongest risk factor is a history of mood or anxiety disorder, especially having active symptoms during pregnancy. As PPD is one of the most common complications of childbirth, it is vital to identify best treatments for optimal maternal, infant, and family outcomes. New understanding of PPD pathophysiology and emerging therapeutics offer the potential for new ways to add to current medications, somatic treatments, and evidence-based psychotherapy. The benefits and potential harms of treatment, including during breastfeeding, are presented.

    更新日期:2019-11-18
  • Cystic Fibrosis: Emerging Understanding and Therapies
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Michael M. Rey, Michael P. Bonk, Denis Hadjiliadis

    Cystic fibrosis (CF) is the most common life-limiting genetic disease in Caucasian patients. Continued advances have led to improved survival, and adults with CF now outnumber children. As our understanding of the disease improves, new therapies have emerged that improve the basic defect, enabling patient-specific treatment and improved outcomes. However, recurrent exacerbations continue to lead to morbidity and mortality, and new pathogens have been identified that may lead to worse outcomes. In addition, new complications, such as CF-related diabetes and increased risk of gastrointestinal cancers, are creating new challenges in management. For patients with end-stage disease, lung transplantation has remained one of the few treatment options, but challenges in identifying the most appropriate patients remain.

    更新日期:2019-11-18
  • Progress in Understanding and Treating Idiopathic Pulmonary Fibrosis
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Jonathan A. Kropski, Timothy S. Blackwell

    This is a time of substantial progress in the evaluation and care of patients with idiopathic pulmonary fibrosis (IPF). In addition to the approval and widespread availability of the first IPF-specific therapies, there have been improvements in imaging interpretation and lung biopsy methods to enable more expeditious and more accurate diagnosis. Recent advances in identifying genetic factors that underlie susceptibility to IPF and affect prognosis have raised the possibility of personalized therapeutic approaches in the future. Further, evolving work is elucidating novel mechanisms influencing epithelial, mesenchymal, and inflammatory cell responses during the injury-repair process, thus advancing understanding of disease pathogenesis. As analytic approaches mature, the field is now poised to harness the power of rapidly advancing “omics” technologies to further accelerate progress.

    更新日期:2019-11-18
  • Current Status of Living Donor Liver Transplantation in the United States
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Samir Abu-Gazala, Kim M. Olthoff

    Adult-to-adult living donor liver transplantation (LDLT) was introduced in response to the shortage of deceased donor liver grafts. The number of adult living donor transplants is increasing due to improved outcomes and increasing need. Advantages of LDLT include optimization of the timing of transplant, better organ quality, and lower rates of recipient mortality compared to staying on the wait list for deceased donor liver transplant. Donor safety remains the major focus when considering LDLT. Recent advancements have supported the increased use of LDLT to help decrease wait list death and improve long-term survival of transplant recipients.

    更新日期:2019-11-18
  • CRISPR Correction of Duchenne Muscular Dystrophy
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Yi-Li Min, Rhonda Bassel-Duby, Eric N. Olson

    The ability to efficiently modify the genome using CRISPR technology has rapidly revolutionized biology and genetics and will soon transform medicine. Duchenne muscular dystrophy (DMD) represents one of the first monogenic disorders that has been investigated with respect to CRISPR-mediated correction of causal genetic mutations. DMD results from mutations in the gene encoding dystrophin, a scaffolding protein that maintains the integrity of striated muscles. Thousands of different dystrophin mutations have been identified in DMD patients, who suffer from a loss of ambulation followed by respiratory insufficiency, heart failure, and death by the third decade of life. Using CRISPR to bypass DMD mutations, dystrophin expression has been efficiently restored in human cells and mouse models of DMD. Here, we review recent progress toward the development of possible CRISPR therapies for DMD and highlight opportunities and potential obstacles in attaining this goal.

    更新日期:2019-11-18
  • Emerging Genetic Therapy for Sickle Cell Disease
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Stuart H. Orkin, Daniel E. Bauer

    The genetic basis of sickle cell disease (SCD) was elucidated >60 years ago, yet current therapy does not rely on this knowledge. Recent advances raise prospects for improved, and perhaps curative, treatment. First, transcription factors, BCL11A and LRF/ZBTB7A, that mediate silencing of the β-like fetal (γ-) globin gene after birth have been identified and demonstrated to act at the γ-globin promoters, precisely at recognition sequences disrupted in rare individuals with hereditary persistence of fetal hemoglobin. Second, transformative advances in gene editing and progress in lentiviral gene therapy provide diverse opportunities for genetic strategies to cure SCD. Approaches include hematopoietic gene therapy by globin gene addition, gene editing to correct the SCD mutation, and genetic manipulations to enhance fetal hemoglobin production, a potent modifier of the clinical phenotype. Clinical trials may soon identify efficacious and safe genetic approaches to the ultimate goal of cure for SCD.

    更新日期:2019-11-18
  • Entering the Modern Era of Gene Therapy
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Xavier M. Anguela, Katherine A. High

    Gene therapies are gaining momentum as promising early successes in clinical studies accumulate and examples of regulatory approval for licensing increase. Investigators are advancing with cautious optimism that effective, durable, and safe therapies will provide benefit to patients—not only those with single-gene disorders but those with complex acquired diseases as well. While the strategies being translated from the lab to the clinic are numerous, this review focuses on the clinical research that has forged the gene therapy field as it currently stands.

    更新日期:2019-11-18
  • Ethics of Human Genome Editing
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Barry S. Coller

    Advances in human genome editing, in particular the development of the clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 method, have led to increasing concerns about the ethics of editing the human genome. In response, the US National Academy of Sciences and the National Academy of Medicine constituted a multidisciplinary, international committee to review the current status and make recommendations. I was a member of that committee, and the core of this review reflects the committee's conclusions. The committee's report, issued in February 2017, recommends the application of current ethical and regulatory standards for gene therapy to somatic (nonheritable) human genome editing. It also recommends allowing experimental germline genome editing to proceed if (a) it is restricted to preventing transmission of a serious disease or condition, (b) the edit is a modification to a common DNA sequence known not to be associated with disease, and (c) the research is conducted under a stringent set of ethical and regulatory requirements. Crossing the so-called red line of germline genome editing raises important bioethical issues, most importantly, serious concern about the potential negative impact on individuals with disabilities. This review highlights some of the major ethical considerations in human genome editing in light of the report's recommendations.

    更新日期:2019-11-18
  • Therapeutic Antisense Oligonucleotides Are Coming of Age
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    C. Frank Bennett

    The first published description of therapeutic applications of antisense oligonucleotide (ASO) technology occurred in the late 1970s and was followed by the founding of commercial companies focused on developing antisense therapeutics in the late 1980s. Since the late 1980s, there has been steady progress in improving the technology platform, taking advantage of advances in oligonucleotide chemistry and formulations as well as increased understanding of the distribution and safety of ASOs. There are several approved ASO drugs and a broad pipeline in development. In addition, advances in understanding human disease, including the genetic basis for most monogenic diseases and the availability of the full human genome sequence, have created numerous therapeutic applications for the technology. I summarize the state of the technology and highlight how advances in the technology position ASOs to be an important contributor to future medicines.

    更新日期:2019-11-18
  • Sodium–Glucose Cotransporter–2 (SGLT-2) Inhibitors and the Treatment of Type 2 Diabetes
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Caroline K. Kramer, Bernard Zinman

    Clinical studies evaluating the cardiovascular safety/impact of sodium–glucose cotransporter–2 (SGLT-2) inhibitors demonstrated a reduction in major adverse cardiovascular events driven primarily by a reduced cardiovascular mortality in individuals with type 2 diabetes and previous cardiovascular disease. These somewhat unexpected results are coupled with SGLT-2 inhibitors’ known acute effect of improvement in glycemia, reduction in blood pressure, and weight loss. In this review, we summarize the mechanism of action of SGLT-2 inhibitors, the metabolic effects of this class of medication, and the remarkable results of cardiovascular safety trials. In addition, we discuss adverse effects associated with these medications and the current recommendations for the use of these agents in the management of diabetes.

    更新日期:2019-11-18
  • Clinical Application and Potential of Fecal Microbiota Transplantation
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    R.E. Ooijevaar, E.M. Terveer, H.W. Verspaget, E.J. Kuijper, J.J. Keller

    Fecal microbiota transplantation (FMT) is a well-established treatment for recurrent Clostridioides difficile infection. FMT has become a more readily available and useful new treatment option as a result of stool banks. The current state of knowledge indicates that dysbiosis of the gut microbiota is implicated in several disorders in addition to C. difficile infection. Randomized controlled studies have shown FMT to be somewhat effective in treating ulcerative colitis, irritable bowel syndrome, and hepatic encephalopathy. In addition, FMT has been beneficial in treating several other conditions, such as the eradication of multidrug-resistant organisms and graft-versus-host disease. We expect that FMT will soon be implemented as a treatment strategy for several new indications, although further studies are needed.

    更新日期:2019-11-18
  • Gastric Cancer Etiology and Management in Asia and the West
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Ashley E. Russo, Vivian E. Strong

    Regional variation in treatment paradigms for gastric adenocarcinoma has attracted a great deal of interest. Between Asia and the West, major differences have been identified in tumor biology, implementation of screening programs, extent of surgical lymphadenectomy, and routine use of neoadjuvant versus adjuvant treatment strategies. Minimally invasive techniques, including both laparoscopic and robotic platforms, have been studied in both regions, with attention to safety, feasibility, and long-term oncologic outcomes. The purpose of this review is to discuss advances in the understanding of the etiology and underlying biology of gastric cancer, as well as the current state of management, focusing on the differences between Asia and the West.

    更新日期:2019-11-18
  • Active Surveillance as First-Line Management of Papillary Microcarcinoma
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Yasuhiro Ito, Akira Miyauchi

    Papillary thyroid microcarcinoma (PMC) is defined as papillary thyroid carcinoma ≤10 mm. Active surveillance of PMC without high-risk features, such as clinical node metastasis, distant metastasis, and clinical evidence of significant extrathyroid extension, was initiated in two Japanese hospitals in the mid-1990s. This strategy was incorporated into guidelines in Japan in 2010 and in the United States in 2015. In studies conducted by the two hospitals, most PMCs grew very slowly or did not grow, and none of the patients during active surveillance showed distant metastasis or died of thyroid carcinoma. Furthermore, none of the patients who underwent surgery after progression signs were detected showed significant recurrence. Therefore, we conclude that active surveillance should be the first line in management of low-risk PMC, because it is safer and less costly than immediate surgery. Active surveillance helps in avoiding adverse events of surgery and is an economical strategy.

    更新日期:2019-11-18
  • Expanding Therapeutic Opportunities for Hematopoietic Stem Cell Transplantation: T Cell Depletion as a Model for the Targeted Allograft
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Christina Cho, Miguel-Angel Perales

    Allogeneic hematopoietic cell transplantation is a fundamental part of the treatment of hematologic malignancies and marrow failure syndromes, but complications including graft-versus-host disease, prolonged immune deficiency and infection, and organ toxicities, as well as relapse, remain obstacles to improved overall survival. As the cellular characteristics of the allograft can exert significant impact on outcomes, the development of more strategically designed grafts represents a rich area for therapeutic intervention. We describe the use of ex vivo T cell–depleted grafts as a model for the targeted graft and review evolving knowledge and approaches for further refinement of allografts to improve patient outcomes.

    更新日期:2019-11-18
  • Harnessing Tumor Mutations for Truly Individualized Cancer Vaccines
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Mathias Vormehr, Özlem Türeci, Ugur Sahin

    T cells are key effectors of anticancer immunity. They are capable of distinguishing tumor cells from normal ones by recognizing major histocompatibility complex–bound cancer-specific peptides. Accumulating evidence suggests that peptides associated with T cell–mediated tumor rejection arise predominantly from somatically mutated proteins and are unique to every patient's tumor. Knowledge of an individual's cancer mutanome (the entirety of cancer mutations) allows harnessing this enormous tumor cell–specific repertoire of highly immunogenic antigens for individualized cancer vaccines. This review outlines the preclinical and clinical state of individualized cancer vaccine development and the challenges ahead.

    更新日期:2019-11-18
  • New Hope for Therapeutic Cancer Vaccines in the Era of Immune Checkpoint Modulation
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Michael A. Curran, Bonnie S. Glisson

    The driver and passenger mutations accumulated in the process of malignant transformation offer an adequate spectrum of immune visible alterations to the cellular proteome and resulting peptidome to render these cancers targetable—and, in theory, rejectable—by the host T cell immune response. In addition, cancers often overexpress tissue-specific and developmental antigens to which immune tolerance is incomplete. Sometimes, virally transferred oncogenes drive malignant transformation and remain expressed throughout the cancer. Despite this state of antigenic sufficiency, cancer grows progressively and overcomes all efforts of the host immune system to contain it. While therapeutic cancer vaccination can mobilize high frequencies of tumor-specific T cells, these responses remain subject to intratumoral attenuation. Antibody modulation of T cell function through checkpoint blockade or costimulatory activation can restore survival, proliferation, and effector function to these tumor-infiltrating T cells and convert otherwise subtherapeutic vaccines into potentially curative cancer immunotherapeutics.

    更新日期:2019-11-18
  • PD-1 Blockade in Early-Stage Lung Cancer
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Samuel Rosner, Joshua E. Reuss, Patrick M. Forde

    Early-stage non–small cell lung cancer is a potentially curable disease, but with relapse rates exceeding 50% with standard treatments, this is a patient population in critical need of therapy innovation. Immunotherapy with immune checkpoint blockade has revolutionized the treatment strategy for advanced lung cancer. However, the role of this therapy in earlier-stage disease is largely unknown. The study of immunotherapy in earlier-stage disease has many advantages, including assessment of pathologic response and incorporation of translational scientific analyses to evaluate antitumor immune responses. Multiple clinical trials are currently under way, with promising early results.

    更新日期:2019-11-18
  • Redirected T Cell Cytotoxicity in Cancer Therapy
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Raphael A. Clynes, John R. Desjarlais

    Bispecific antibodies that recruit and redirect T cells to attack tumor cells have tremendous potential for the treatment of various malignancies. In general, this class of therapeutics, known as CD3 bispecifics, promotes tumor cell killing by cross-linking a CD3 component of the T cell receptor complex with a tumor-associated antigen on the surface of the target cell. Importantly, this mechanism does not rely on a cognate interaction between the T cell receptor and a peptide:HLA complex, thereby circumventing HLA (human leukocyte antigen) restriction. Hence, CD3 bispecifics may find a key role in addressing tumors with low neoantigen content and/or low inflammation, and this class of therapeutics may productively combine with checkpoint blockade. A wide array of formats and optimization approaches has been developed, and a wave of CD3 bispecifics is proceeding into human clinical trials for a range of indications, with promising signs of therapeutic activity.

    更新日期:2019-11-18
  • Prostate Magnetic Resonance Imaging: Lesion Detection and Local Staging
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Baris Turkbey, Peter L. Choyke

    Dramatic changes in the use of prostate magnetic resonance imaging (MRI) have occurred in the last decade. The recognition that MRI detects and localizes cancers with reasonable accuracy led to the development of directed biopsies. These image-guided biopsies have a higher sensitivity for clinically significant cancers and a lower sensitivity for indolent disease. Prospective trials provide level 1 evidence supporting the use of prostate MRI. For local staging, while the specificity of prostate MRI is high, its sensitivity is lacking for microscopic extraprostatic extension. Computer-aided diagnosis of prostate MRI promises to bring the diagnostic power of MRI to nonexpert readers and thus further integrate MRI into the diagnostic workup.

    更新日期:2019-11-18
  • Imaging of Prostate-Specific Membrane Antigen with Small-Molecule PET Radiotracers: From the Bench to Advanced Clinical Applications
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Steven P. Rowe, Michael A. Gorin, Martin G. Pomper

    In recent years, small-molecule inhibitors of prostate-specific membrane antigen (PSMA) labeled with radionuclides that allow for positron emission tomography (PET) imaging have been extensively studied in many clinical contexts in men with prostate cancer (PCa). The high sensitivity and specificity of these agents for identifying sites of PCa has quickly led to their widespread adoption as a de facto clinical standard of care throughout much of the world. PSMA-targeted PET radiotracers have been particularly well-studied in preoperatively staging men with high-risk PCa, evaluating biochemical recurrence following definitive therapy, and guiding metastasis-directed therapy in patients suspected of having oligorecurrent/oligometastatic disease. Furthermore, the expression of PSMA on the tumor neovasculature of many nonprostate malignancies has enabled a burgeoning subfield concentrated on delineating the potential utility of PSMA-targeted PET agents for imaging other cancers. In this review, we highlight the preclinical development of key small molecules that are now being clinically utilized for PCa imaging, discuss the roles of PSMA-targeted agents in guiding patient management, and consider the role these compounds may play in imaging nonprostate cancers.

    更新日期:2019-11-18
  • Treatment of Advanced Prostate Cancer
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Min Yuen Teo, Dana E. Rathkopf, Philip Kantoff

    The therapeutic landscape of prostate cancer has been transformed over the last decade by new therapeutics, advanced functional imaging, next-generation sequencing, and better use of existing therapies in early-stage disease. Until 2004, progression on androgen deprivation therapy for metastatic disease was treated with the addition of secondary hormonal manipulation; in the last decade, six systemic agents have been approved for the treatment of castration-resistant prostate cancer. We review clinical trials and survival benefit for these therapies and assess how the understanding of the disease shifted as these therapies were developed. We also discuss advances in noncastrate disease states, identification of biomarkers for prognosis and treatment selection, and opportunities in locoregional therapy to delay androgen deprivation therapy.

    更新日期:2019-11-18
  • Abbreviated Magnetic Resonance Imaging (MRI) for Breast Cancer Screening: Rationale, Concept, and Transfer to Clinical Practice
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Christiane K. Kuhl

    Given the increasing understanding of cancer as a heterogeneous group of diseases, detection methods should offer a sensitivity profile that ensures perfect sensitivity for biologically important cancers while screening out self-limiting pseudocancers. However, mammographic screening is biased toward detection of ductal carcinoma in situ and slowly growing cancers—and thus frequently fails to detect biologically aggressive cancers. This explains the persistently high rates of interval cancers and high rates of breast cancer mortality observed in spite of decades of mammographic screening. Magnetic resonance imaging (MRI), in contrast, has a sensitivity profile that matches clinical needs. Conventional MRI is not suitable for population-wide screening due to high cost, limited tolerability, and lack of availability. We introduced abbreviated MRI in 2014. Abbreviated MRI will change the way MRI is used in clinical medicine. This article describes the rationale to use MRI in general, and abbreviated MRI in particular, for breast cancer screening.

    更新日期:2019-11-18
  • New Drugs in Multiple Myeloma
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-01-28
    Chutima Kunacheewa, Robert Z. Orlowski

    Multiple myeloma is diagnosed in over 100,000 patients each year worldwide, has an increasing incidence and prevalence in many regions, and follows a relapsing course, making it a significant and growing healthcare challenge. Recent basic, translational, and clinical studies have expanded our therapeutic armamentarium, which now consists of alkylating agents, corticosteroids, deacetylase inhibitors, immunomodulatory agents, monoclonal antibodies, and proteasome inhibitors. New drugs in these categories, and additional agents, including both small and large molecules, as well as cellular therapies, are under development that promise to further expand our capabilities and bring us closer to the cure of this plasma cell dyscrasia.

    更新日期:2019-11-18
  • Current Approaches to Germline Cancer Genetic Testing.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-11-23
    Elena M Stoffel,John M Carethers

    The prevalence of genetic predisposition to cancer is greater than initially appreciated, yet most affected individuals remain undiagnosed. Deleterious germline variants in cancer predisposition genes are implicated in 1 in 10 cases of advanced cancer. Next-generation sequencing technologies have made germline and tumor DNA sequencing more accessible and less expensive. Expanded access to clinical genetic testing will improve identification of individuals with genetic predisposition to cancer and provide opportunities to effectively reduce morbidity through precision cancer therapies and surveillance. Cross-disciplinary clinical education in genomic medicine is needed to translate advances in genomic medicine into improved health outcomes. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Ablation Therapy for Refractory Ventricular Arrhythmias.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-11-21
    Pasquale Santangeli,Francis E Marchlinski

    Recurrent ventricular arrhythmias (VAs) are a leading cause of cardiovascular morbidity and mortality. In the last three decades, important advancements have occurred in the understanding of the mechanisms of recurrent VAs, their prognostic implications in different clinical contexts, and their treatment options. VAs occur in structurally normal hearts as well as in patients with underlying heart disease, but the latter group has a particularly high risk of recurrent VAs. Catheter ablation offers the possibility of cure for a substantial proportion of patients. Research has focused on identifying optimal targets for ablation, correlating the underlying structural abnormalities with the site of origin of VAs, and determining the optimal procedural approach. Ablation therapy can be life-saving in select patients with high burden of repetitive VAs or advanced heart failure syndromes. This article focuses on clinical aspects of catheter ablation of VAs, particularly the selection and clinical management of patients undergoing catheter ablation procedures and expected outcomes. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • New Therapies for Emerging Endotypes of Asthma.
    Annu. Rev. Med. (IF 10.091) Pub Date : null
    Geoffrey Lowell Chupp,Ravdeep Kaur,Anne Mainardi

    The presentation, pathobiology, and prognosis of asthma are highly heterogeneous and challenging for clinicians to diagnose and treat. In addition to the adaptive immune response that underlies allergic inflammation, innate immune mechanisms are increasingly recognized to be critical mediators of the eosinophilic airway inflammation present in most patients with asthma. Efforts to classify patients by severity and immune response have identified a number of different clinical and immune phenotypes, indicating that the innate and adaptive immune responses are differentially active among patients with the disease. Advances in the detection of these subgroups using clinical characteristics and biomarkers have led to the successful development of targeted biologics. This has moved us to a more personalized approach to managing asthma. Here we review the emerging endotypes of asthma and the biologics that have been developed to treat them. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2009-07-31
    David J Kuter

    Although the thrombopoietin receptor was discovered in 1991 and thrombopoietin (TPO) was purified in 1994, the development of a clinically useful TPO was hampered by the appearance of neutralizing antibodies to some forms of recombinant TPO. However, in 2008 two new drugs that mimic the effect of TPO became available to treat thrombocytopenia. Romiplostim is a TPO peptide mimetic given by subcutaneous injection that activates the TPO receptor by binding to the distal hematopoietic receptor domain just like TPO. Eltrombopag is a TPO nonpeptide mimetic administered orally that activates the TPO receptor by binding to the transmembrane domain. Both increase the platelet count in healthy humans as well as in >80% of patients with immune thrombocytopenic purpura (ITP). Although initially restricted to the second-line treatment of ITP, both agents could help treat many thrombocytopenic disorders. Both agents are well tolerated, with mild headache being the most common complaint. Potential long-term complications include thrombosis, increased bone marrow reticulin, rebound worsening of thrombocytopenia upon discontinuation, and increased blast formation. Ongoing studies should establish the incidence of these complications and determine the efficacy of these new agents in a variety of other thrombocytopenic conditions.

    更新日期:2019-11-01
  • Prevention of HIV Transmission and the HPTN 052 Study.
    Annu. Rev. Med. (IF 10.091) Pub Date : null
    Myron S Cohen,Theresa Gamble,Marybeth McCauley

    The HIV Prevention Trials Network 052 study (HPTN 052) was a clinical trial designed to determine whether early treatment for HIV infection prevented transmission of the virus in couples where one partner was infected with HIV and the other was not, referred to as HIV serodiscordant or serodifferent couples. The study enrolled 1,763 couples at 13 sites in 9 countries in Asia, Africa, and the Americas. HPTN 052 demonstrated a minimum of 96% reduction of HIV in heterosexual couples ascribed to antiretroviral treatment; early treatment of HIV significantly reduced other infections in the HIV-infected subjects. This study, in conjunction with similar research, led to significant changes in international HIV treatment guidelines and the concept of treatment as prevention (TasP). This article provides the scientific background and history of how HPTN 052 came into being, the challenges it faced, and the ultimate impact it had on the fields of HIV treatment and prevention. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Hemochromatosis: genetics and pathophysiology.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2006-01-18
    Ernest Beutler

    A number of genetic disorders can result in the accumulation of excess iron in the body. These causes of hereditary hemochromatosis include defects in genes encoding HFE, transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin. Hepcidin, with its cognate receptor, ferroportin, has emerged as a central regulator of iron homeostasis; all of the known causes of hemochromatosis appear to prevent this system from functioning normally. The most common form of primary hemochromatosis is that caused by C282Y mutation of the HFE gene. This mutation is most prevalent among Northern Europeans. Although the frequency of the homozygous genotype is approximately 5 per 1000, the disease itself is quite rare because the clinical penetrance of the genotype is very low.

    更新日期:2019-11-01
  • Topical Microbicides in HIV Prevention: State of the Promise.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-10-16
    Jared M Baeten,Craig W Hendrix,Sharon L Hillier

    HIV topical microbicides are products with anti-HIV activity, generally incorporating a direct-acting antiretroviral agent, that when applied to the vagina or rectum have the potential to prevent the sexual acquisition of HIV in women and men. Topical microbicides may meet the prevention needs of individuals and groups for whom oral daily forms of pre-exposure prophylaxis (PrEP) have not been acceptable. Microbicides can provide personal control over HIV prevention and offer the possibility of discreet use, qualities that may be particularly important for receptive partners in sexual relationships such as women and transgender women and men, who together account for the clear majority of new HIV infections worldwide. Although the promise of such a product emerged nearly three decades ago, proof of concept has been demonstrated only within the last decade. A robust pipeline of microbicidal gels, films, inserts, and rings has been evaluated in multiple studies among at-risk women and men, and refinement of products for ease of use, reversibility, and high safety is the priority for the field. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Sex Hormones and Prostate Cancer.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-10-16
    Richard J Auchus,Nima Sharifi

    The prostate is an androgen-dependent organ that develops only in male mammals. Prostate cancer is the most common nonskin malignancy in men and the second leading cause of cancer deaths. Metastatic prostate cancer initially retains its androgen dependence, and androgen-deprivation therapy often leads to disease control; however, the cancer inevitably progresses despite treatment as castration-resistant prostate cancer, the lethal form of the disease. Although it was assumed that the cancer became androgen independent during this transition, studies over the last two decades have shown that these tumors evade treatment via mechanisms that augment acquisition of androgens from circulating precursors, increase sensitivity to androgens and androgen precursors, bypass the androgen receptor, or a combination of these mechanisms. This review summarizes the history of prostate cancer research leading to the contemporary view of androgen dependence for prostate cancers and the current treatment approaches based on this modern paradigm. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Is a Universal Influenza Virus Vaccine Possible?
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-10-11
    Raffael Nachbagauer,Peter Palese

    Influenza viruses remain a severe burden to human health because of their contribution to overall morbidity and mortality. Current seasonal influenza virus vaccines do not provide sufficient protection to alleviate the annual impact of influenza and cannot confer protection against potentially pandemic influenza viruses. The lack of protection is due to rapid changes of the viral epitopes targeted by the vaccine and the often suboptimal immunogenicity of current immunization strategies. Major efforts to improve vaccination approaches are under way. The development of a universal influenza virus vaccine may be possible by combining the lessons learned from redirecting the immune response toward conserved viral epitopes, as well as the use of adjuvants and novel vaccination platforms. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • The JAK-STAT pathway: impact on human disease and therapeutic intervention.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2015-01-15
    John J O'Shea,Daniella M Schwartz,Alejandro V Villarino,Massimo Gadina,Iain B McInnes,Arian Laurence

    The Janus kinase (JAK)-signal transducer of activators of transcription (STAT) pathway is now recognized as an evolutionarily conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. This pathway provides an elegant and remarkably straightforward mechanism whereby extracellular factors control gene expression. It thus serves as a fundamental paradigm for how cells sense environmental cues and interpret these signals to regulate cell growth and differentiation. Genetic mutations and polymorphisms are functionally relevant to a variety of human diseases, especially cancer and immune-related conditions. The clinical relevance of the pathway has been confirmed by the emergence of a new class of therapeutics that targets JAKs.

    更新日期:2019-11-01
  • IL-1 blockade in autoinflammatory syndromes.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2014-01-16
    Adriana A Jesus,Raphaela Goldbach-Mansky

    Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. Pathogenic variants in two interleukin-1 (IL-1)-regulating genes, NLRP3 and IL1RN, cause two severe and early-onset autoinflammatory syndromes, CAPS (cryopyrin associated periodic syndromes) and DIRA (deficiency of IL-1 receptor antagonist). The discovery of the mutations that cause CAPS and DIRA led to clinical and basic research that uncovered the key role of IL-1 in an extended spectrum of immune dysregulatory conditions. NLRP3 encodes cryopyrin, an intracellular "molecular sensor" that forms a multimolecular platform, the NLRP3 inflammasome, which links "danger recognition" to the activation of the proinflammatory cytokine IL-1β. The success and safety profile of drugs targeting IL -1 in the treatment of CAPS and DIRA have encouraged their wider use in other autoinflammatory syndromes including the classic hereditary periodic fever syndromes (familial Mediterranean fever, TNF receptor-associated periodic syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome) and additional immune dysregulatory conditions that are not genetically well defined, including Still's, Behcet's, and Schnitzler diseases. The fact that the accumulation of metabolic substrates such as monosodium urate, ceramide, cholesterol, and glucose can trigger the NLRP3 inflammasome connects metabolic stress to IL-1β-mediated inflammation and provides a rationale for therapeutically targeting IL-1 in prevalent diseases such as gout, diabetes mellitus, and coronary artery disease.

    更新日期:2019-11-01
  • Male circumcision: a globally relevant but under-utilized method for the prevention of HIV and other sexually transmitted infections.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2013-10-12
    Aaron A R Tobian,Seema Kacker,Thomas C Quinn

    Randomized trials have demonstrated that male circumcision (MC) reduces heterosexual acquisition of HIV, herpes simplex virus type 2, human papillomavirus (HPV), and genital ulcer disease among men, and it reduces HPV, genital ulcer disease, bacterial vaginosis, and trichomoniasis among female partners. The pathophysiology behind these effects is multifactorial, relying on anatomic and cellular changes. MC is cost effective and potentially cost saving in both the United States and Africa. The World Health Organization and Joint United Nations Program on HIV/AIDS proposed reaching 80% MC coverage in HIV endemic countries, but current rates fall far behind targets. Barriers to scale-up include supply-side and demand-side challenges. In the United States, neonatal MC rates are decreasing, but the American Academy of Pediatrics now recognizes the medical benefits of MC and supports insurance coverage. Although MC is a globally valuable tool to prevent HIV and other sexually transmitted infections, it is underutilized. Further research is needed to address barriers to MC uptake.

    更新日期:2019-11-01
  • Immunogenetics of spontaneous control of HIV.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2012-01-18
    Mary Carrington,Bruce D Walker

    Host genetic variation is presently estimated to account for about one-fourth of the observed differences in control of HIV across infected individuals. Genome-wide association studies have confirmed that polymorphism within the HLA class I locus is the primary host genetic contributor to determining outcome after infection. Here we progress beyond the genetic associations alone to consider the functional explanations for these correlations. In this process, the complex and multidimensional effects of HLA molecules in viral disease become apparent.

    更新日期:2019-11-01
  • Telomeres, atherosclerosis, and the hemothelium: the longer view.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2011-10-25
    Abraham Aviv,Daniel Levy

    The model we propose to explain the links between atherosclerosis and telomere dynamics (birth telomere length and its age-dependent shortening) in leukocytes takes cues from three facts: atherosclerosis is a disease of the vascular endothelium; the hematopoietic system and the vascular endothelium share a common embryonic origin; interindividual variation in leukocyte telomere length (LTL) in the general population has a genetic explanation. The model posits that LTL dynamics mirror telomere dynamics in hematopoietic stem cells (HSCs), where telomere length is an index of HSC reserves. Diminished HSC reserves at birth, their accelerated attrition rate afterward, or both are are reflected in shortened LTL during adulthood-a phenomenon that confers increased risk for atherosclerosis. We explain how telomere length in HSCs serves as both a biomarker of atherosclerosis and a determinant of its development. Our model comes down to this proposition: Shortened LTL predicts increased atherosclerotic risk because the injurious component of atherosclerosis exceeds the repair capacity of HSC reserves, which largely depend on HSC telomere length.

    更新日期:2019-11-01
  • The HapMap and genome-wide association studies in diagnosis and therapy.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2009-07-28
    Teri A Manolio,Francis S Collins

    The International HapMap Project produced a genome-wide database of human genetic variation for use in genetic association studies of common diseases. The initial output of these studies has been overwhelming, with over 150 risk loci identified in studies of more than 60 common diseases and traits. These associations have suggested previously unsuspected etiologic pathways for common diseases that will be of use in identifying new therapeutic targets and developing targeted interventions based on genetically defined risk. Here we examine the development and application of the HapMap to genome-wide association (GWA) studies; present and future technologies for GWA research; current major efforts in GWA studies; successes and limitations of the GWA approach in identifying polymorphisms related to complex diseases; data release and privacy polices; use of these findings by clinicians, the public, and academic physicians; and sources of ongoing authoritative information on this rapidly evolving field.

    更新日期:2019-11-01
  • Emerging concepts in the immunopathogenesis of AIDS.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2008-10-25
    Daniel C Douek,Mario Roederer,Richard A Koup

    There is an intense interplay between HIV and the immune system, and the literature is replete with studies describing various immunological phenomena associated with HIV infection. Many of these phenomena seem too broad in scope to be attributable either to HIV-infected cells or to the HIV-specific immune response. Recently, a more fundamental understanding of how HIV affects various T cells and T cell compartments has emerged. This review covers the role of immune activation in HIV immunopathogenesis, how that activation could be mediated directly by HIV replicating within and damaging the gut mucosal barrier, how HIV affects multiple T cell functions and phenotypes, and how chronic HIV replication induces immune modulatory pathways to negatively regulate certain functions in HIV-specific T cells.

    更新日期:2019-11-01
  • Inherited mitochondrial diseases of DNA replication.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2007-09-26
    William C Copeland

    Mitochondrial genetic diseases can result from defects in mitochondrial DNA (mtDNA) in the form of deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These mutations may be spontaneous, maternally inherited, or a result of inherited nuclear defects in genes that maintain mtDNA. This review focuses on our current understanding of nuclear gene mutations that produce mtDNA alterations and cause mitochondrial depletion syndrome (MDS), progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). To date, all of these etiologic nuclear genes fall into one of two categories: genes whose products function directly at the mtDNA replication fork, such as POLG, POLG2, and TWINKLE, or genes whose products supply the mitochondria with deoxynucleotide triphosphate pools needed for DNA replication, such as TK2, DGUOK, TP, SUCLA2, ANT1, and possibly the newly identified MPV17.

    更新日期:2019-11-01
  • Male Hormonal Contraception.
    Annu. Rev. Med. (IF 10.091) Pub Date : null
    Arthi Thirumalai,Stephanie T Page

    The economic and public health burdens of unplanned pregnancies are evident globally. Since the introduction of the condom >300 years ago, assumptions about male willingness to participate in contraception, as well as concerns about failure rates and side effects, have stagnated the development of additional reversible male contraceptives. However, changing attitudes and recent research advances have generated renewed interest in developing reversible male contraceptives. To achieve effective and reversible suppression of spermatogenesis, male hormonal contraception relies on suppression of testicular testosterone and sperm production using an androgen-progestin combination. While these may be associated with side effects-changes in libido, weight, hematocrit, and cholesterol-recently, novel androgens and progestins have shown promise for a "male pill" with reduced side effects. Here we summarize landmark studies in male contraceptive development, showcase the most recent advances, and look into the future of this field, which has the potential to greatly impact global public health. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • New Frontiers in Osteoporosis Therapy.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-09-12
    Cheng Cheng,Kelly Wentworth,Dolores M Shoback

    Current osteoporosis medications reduce fractures significantly but have rare and serious adverse effects (osteonecrosis of the jaw, atypical femoral fractures) that may limit their safety for long-term use. Insights from basic bone biology and genetic disorders have led to recent advances in therapeutics for osteoporosis. New approaches now in clinical use include the antisclerostin monoclonal antibody romosozumab, as well as the parathyroid hormone-related peptide analog abaloparatide. Clinical trial data show significant antifracture benefits with recently approved romosozumab. Studies using abaloparatide build on our longstanding experience with teriparatide and the importance of consolidating the bone mineral density gains achieved from an anabolic agent by following it with an antiresorptive. Combination and sequential treatments using osteoporosis medications with different mechanisms of action have also been tested with promising results. On the horizon is the potential for cell-based therapies (e.g., mesenchymal stem cells) and drugs that target the elimination of senescent cells in the bone microenvironment. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • A Crucial Role for Diet in the Relationship Between Gut Microbiota and Cardiometabolic Disease.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-09-04
    Ilias Attaye,Sara-Joan Pinto-Sietsma,Hilde Herrema,Max Nieuwdorp

    Cardiometabolic disease (CMD), such as type 2 diabetes mellitus and cardiovascular disease, contributes significantly to morbidity and mortality on a global scale. The gut microbiota has emerged as a potential target to beneficially modulate CMD risk, possibly via dietary interventions. Dietary interventions have been shown to considerably alter gut microbiota composition and function. Moreover, several diet-derived microbial metabolites are able to modulate human metabolism and thereby alter CMD risk. Dietary interventions that affect gut microbiota composition and function are therefore a promising, novel, and cost-efficient method to reduce CMD risk. Studies suggest that fermentable carbohydrates can beneficially alter gut microbiota composition and function, whereas high animal protein and high fat intake negatively impact gut microbiota function and composition. This review focuses on the role of macronutrients (i.e., carbohydrate, protein, and fat) and dietary patterns (e.g., vegetarian/vegan and Mediterranean diet) in gut microbiota composition and function in the context of CMD. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Genome Editing and Hematologic Malignancy.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-08-31
    Brian T Emmer,David Ginsburg

    The modern genomic era has seen remarkable advancement in our understanding of the molecular basis for disease, yet translation of basic discoveries into new disease treatments has arguably lagged behind. Recently, breakthroughs in genome editing technologies have created hope for their potential to directly treat the genetic causes of disease. Like any therapeutic intervention, genome editing should be considered in light of its potential risks and benefits. In this review, we highlight the promise of genome editing therapies, as well as the conceptual and technical barriers to their clinical application, with a special emphasis on hematologic malignancies. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Fecal DNA Testing for Colorectal Cancer Screening.
    Annu. Rev. Med. (IF 10.091) Pub Date : null
    John M Carethers

    Fecal (or stool) DNA examination is a noninvasive strategy recommended by several medical professional societies for colorectal cancer (CRC) screening in average-risk individuals. Fecal DNA tests assay stool for human DNA shed principally from the colon. Colonic lesions such as adenomatous and serrated polyps and cancers exfoliate cells containing neoplastically altered DNA that may be detected by sensitive assays that target specific genetic and epigenetic biomarkers to discriminate neoplastic lesions from non-neoplastic tissue. Cross-sectional validation studies confirmed initial case-control studies' assessment of performance of an optimized multitarget stool DNA (mt-sDNA) test, leading to approval by the US Food and Drug Administration in 2014. Compared to colonoscopy, mt-sDNA showed sensitivity of 92% for detection of CRC, much higher than the 74% sensitivity of another recommended noninvasive strategy, fecal immunochemical testing (FIT). Detections of advanced adenomas and sessile serrated polyps were higher with mt-sDNA than FIT (42% versus 24% and 42% versus 5%, respectively), but overall specificity for all lesions was lower (87% versus 95%). The mt-sDNA test increases patient life-years gained in CRC screening simulations, but its cost relative to other screening strategies needs to be reduced by 80-90% or its sensitivity for polyp detection enhanced to be cost effective. Noninvasive CRC screening strategies such as fecal DNA, however, have the potential to significantly increase national screening rates due to their noninvasive nature and convenience for patients. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • The FDA critical path initiative and its influence on new drug development.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2008-01-12
    Janet Woodcock,Raymond Woosley

    Societal expectations about drug safety and efficacy are rising while productivity in the pharmaceutical industry is falling. In 2004, the US Food and Drug Administration introduced the Critical Path Initiative with the intent of modernizing drug development by incorporating recent scientific advances, such as genomics and advanced imaging technologies, into the process. An important part of the initiative is the use of public-private partnerships and consortia to accomplish the needed research. This article explicates the reasoning behind the Critical Path Initiative and discusses examples of successful consortia.

    更新日期:2019-11-01
  • The Clinical Spectrum of PTEN Mutations.
    Annu. Rev. Med. (IF 10.091) Pub Date : null
    Lamis Yehia,Emma Keel,Charis Eng

    PTEN is a tumor suppressor gene that classically dampens the PI3K/AKT/mTOR growth-promoting signaling cascade. PTEN dysfunction causes dysregulation of this and other pathways, resulting in overgrowth. Cowden syndrome, a hereditary cancer predisposition and overgrowth disorder, was the first Mendelian condition associated with germline PTEN mutations. Since then, significant advances by the research and medical communities have elucidated how clinical phenotypic manifestations result from the underlying germline PTEN mutations. With time, it became evident that PTEN mutations can result in a broad phenotypic spectrum, causing seemingly disparate disorders from cancer to autism. Hence, the umbrella term of PTEN hamartoma tumor syndrome (PHTS) was coined. Timely diagnosis and understanding the natural history of PHTS are vital because early recognition enables gene-informed management, particularly as related to high-risk cancer surveillance and addressing the neurodevelopmental symptoms. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Postural Orthostatic Tachycardia Syndrome: Mechanisms and New Therapies.
    Annu. Rev. Med. (IF 10.091) Pub Date : 2019-08-15
    Philip L Mar,Satish R Raj

    Postural orthostatic tachycardia syndrome (POTS) is a clinically heterogeneous disorder with multiple contributing pathophysiologic mechanisms manifesting as symptoms of orthostatic intolerance in the setting of orthostatic tachycardia (increase in heart rate by at least 30 beats per minute upon assuming an upright position) without orthostatic hypotension. The three major pathophysiologic mechanisms include partial autonomic neuropathy, hypovolemia, and hyperadrenergic state. Patients often will exhibit overlapping characteristics from more than one of these mechanisms. The approach to the treatment of POTS centers on treating the underlying pathophysiologic mechanism. Stockings, abdominal binders, and vasoconstrictors are used to enhance venous return in partial neuropathic POTS. Exercise and volume expansion are the main treatment strategies for hypovolemic POTS. For hyperadrenergic POTS, beta-blockers and avoidance of norepinephrine-reuptake inhibitors is important. Attempts should be made to discern which pathophysiologic mechanism(s) may be afflicting patients so that treatment regimens can be individualized. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
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