Current Approaches to Germline Cancer Genetic Testing.
Abstract 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. Cro...
Source: Annual Review of Medicine - November 22, 2019 Category: General Medicine Authors: Stoffel EM, Carethers JM Tags: Annu Rev Med Source Type: research

Ablation Therapy for Refractory Ventricular Arrhythmias.
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. PMID: 31747356 [PubMed - as supplied by publisher] (Source: Annual Review of Medicine)
Source: Annual Review of Medicine - November 20, 2019 Category: General Medicine Authors: Santangeli P, Marchlinski FE Tags: Annu Rev Med Source Type: research

New Therapies for Emerging Endotypes of Asthma.
Abstract 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 d...
Source: Annual Review of Medicine - November 5, 2019 Category: General Medicine Authors: Chupp GL, Kaur R, Mainardi A Tags: Annu Rev Med Source Type: research

Prevention of HIV Transmission and the HPTN 052 Study.
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. PMID: 31652410 [PubMed - as supplied by publisher] (Source: Annual Review of Medicine)
Source: Annual Review of Medicine - October 25, 2019 Category: General Medicine Authors: Cohen MS, Gamble T, McCauley M Tags: Annu Rev Med Source Type: research

Sex Hormones and Prostate Cancer.
Abstract 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 e...
Source: Annual Review of Medicine - October 15, 2019 Category: General Medicine Authors: Auchus RJ, Sharifi N Tags: Annu Rev Med Source Type: research

Topical Microbicides in HIV Prevention: State of the Promise.
Abstract 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...
Source: Annual Review of Medicine - October 15, 2019 Category: General Medicine Authors: Baeten JM, Hendrix CW, Hillier SL Tags: Annu Rev Med Source Type: research

Is a Universal Influenza Virus Vaccine Possible?
Abstract 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 ma...
Source: Annual Review of Medicine - October 10, 2019 Category: General Medicine Authors: Nachbagauer R, Palese P Tags: Annu Rev Med Source Type: research

Male Hormonal Contraception.
Abstract 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 t...
Source: Annual Review of Medicine - September 19, 2019 Category: General Medicine Authors: Thirumalai A, Page ST Tags: Annu Rev Med Source Type: research

New Frontiers in Osteoporosis Therapy.
Abstract 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 abaloparat...
Source: Annual Review of Medicine - September 11, 2019 Category: General Medicine Authors: Cheng C, Wentworth K, Shoback DM Tags: Annu Rev Med Source Type: research

A Crucial Role for Diet in the Relationship Between Gut Microbiota and Cardiometabolic Disease.
Abstract 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, nov...
Source: Annual Review of Medicine - September 3, 2019 Category: General Medicine Authors: Attaye I, Pinto-Sietsma SJ, Herrema H, Nieuwdorp M Tags: Annu Rev Med Source Type: research

Genome Editing and Hematologic Malignancy.
Abstract 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...
Source: Annual Review of Medicine - August 30, 2019 Category: General Medicine Authors: Emmer BT, Ginsburg D Tags: Annu Rev Med Source Type: research

Fecal DNA Testing for Colorectal Cancer Screening.
Abstract 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' a...
Source: Annual Review of Medicine - August 26, 2019 Category: General Medicine Authors: Carethers JM Tags: Annu Rev Med Source Type: research

The Clinical Spectrum of PTEN Mutations.
Abstract 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 phenoty...
Source: Annual Review of Medicine - August 21, 2019 Category: General Medicine Authors: Yehia L, Keel E, Eng C Tags: Annu Rev Med Source Type: research

CD40 Agonist Antibodies in Cancer Immunotherapy.
Abstract CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 antibodies of varying formulations have been evaluated in the clinic and found to be tolerable and feasible. Administration is associated with mild to moderate (but transient) cytokine release syndrome, readily managed in the outpatient setting. Antitumor activity with or without anti-CTLA4 monoclonal antibody (mAb) therapy has been observed in patients with m...
Source: Annual Review of Medicine - August 14, 2019 Category: General Medicine Authors: Vonderheide RH Tags: Annu Rev Med Source Type: research

Postural Orthostatic Tachycardia Syndrome: Mechanisms and New Therapies.
Abstract 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 P...
Source: Annual Review of Medicine - August 14, 2019 Category: General Medicine Authors: Mar PL, Raj SR Tags: Annu Rev Med Source Type: research

Structure-Based Vaccine Antigen Design.
Abstract 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...
Source: Annual Review of Medicine - January 27, 2019 Category: General Medicine Authors: Graham BS, Gilman MSA, McLellan JS Tags: Annu Rev Med Source Type: research

Treatment of Advanced Prostate Cancer.
Abstract 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 ...
Source: Annual Review of Medicine - January 27, 2019 Category: General Medicine Authors: Teo MY, Rathkopf DE, Kantoff P Tags: Annu Rev Med Source Type: research

Ethics of Human Genome Editing.
Abstract 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 ethi...
Source: Annual Review of Medicine - January 27, 2019 Category: General Medicine Authors: Coller BS Tags: Annu Rev Med Source Type: research

Therapeutic Antisense Oligonucleotides Are Coming of Age.
Abstract 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 huma...
Source: Annual Review of Medicine - January 27, 2019 Category: General Medicine Authors: Bennett CF Tags: Annu Rev Med Source Type: research

DNA Methylation and Susceptibility to Autism Spectrum Disorder.
Abstract 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 b...
Source: Annual Review of Medicine - January 27, 2019 Category: General Medicine Authors: Tremblay MW, Jiang YH Tags: Annu Rev Med Source Type: research

New Drugs in Multiple Myeloma.
Abstract 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 und...
Source: Annual Review of Medicine - January 27, 2019 Category: General Medicine Authors: Kunacheewa C, Orlowski RZ Tags: Annu Rev Med Source Type: research

Abbreviated Magnetic Resonance Imaging (MRI) for Breast Cancer Screening: Rationale, Concept, and Transfer to Clinical Practice.
This article describes the rationale to use MRI in general, and abbreviated MRI in particular, for breast cancer screening. PMID: 30691370 [PubMed - in process] (Source: Annual Review of Medicine)
Source: Annual Review of Medicine - January 27, 2019 Category: General Medicine Authors: Kuhl CK Tags: Annu Rev Med Source Type: research

Progress in Understanding and Treating Idiopathic Pulmonary Fibrosis.
Abstract 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,...
Source: Annual Review of Medicine - January 27, 2019 Category: General Medicine Authors: Kropski JA, Blackwell TS Tags: Annu Rev Med Source Type: research

Postpartum Depression: Pathophysiology, Treatment, and Emerging Therapeutics.
Abstract 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 presen...
Source: Annual Review of Medicine - January 27, 2019 Category: General Medicine Authors: Stewart DE, Vigod SN Tags: Annu Rev Med Source Type: research

Imaging of Prostate-Specific Membrane Antigen with Small-Molecule PET Radiotracers: From the Bench to Advanced Clinical Applications.
Abstract 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 ...
Source: Annual Review of Medicine - January 27, 2019 Category: General Medicine Authors: Rowe SP, Gorin MA, Pomper MG Tags: Annu Rev Med Source Type: research

Harnessing Tumor Mutations for Truly Individualized Cancer Vaccines.
Sahin U Abstract 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 ...
Source: Annual Review of Medicine - January 27, 2019 Category: General Medicine Authors: Vormehr M, Türeci Ö, Sahin U Tags: Annu Rev Med Source Type: research

Prostate Magnetic Resonance Imaging: Lesion Detection and Local Staging.
Abstract 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 pr...
Source: Annual Review of Medicine - January 27, 2019 Category: General Medicine Authors: Turkbey B, Choyke PL Tags: Annu Rev Med Source Type: research

Non-Vitamin K Antagonist Oral Anticoagulants in the Treatment of Atrial Fibrillation.
Abstract 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...
Source: Annual Review of Medicine - November 26, 2018 Category: General Medicine Authors: Fanaroff AC, Ohman EM Tags: Annu Rev Med Source Type: research

Entering the Modern Era of Gene Therapy.
Abstract 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. Expected final online publication date for the An...
Source: Annual Review of Medicine - November 26, 2018 Category: General Medicine Authors: Anguela XM, High KA Tags: Annu Rev Med Source Type: research

Clinical Application and Potential of Fecal Microbiota Transplantation.
Abstract 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. 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 eradic...
Source: Annual Review of Medicine - November 7, 2018 Category: General Medicine Authors: Ooijevaar RE, Terveer EM, Verspaget HW, Kuijper EJ, Keller JJ Tags: Annu Rev Med Source Type: research

The Global Landscape of Tuberculosis Therapeutics.
Abstract 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 fo...
Source: Annual Review of Medicine - November 7, 2018 Category: General Medicine Authors: Tornheim JA, Dooley KE Tags: Annu Rev Med Source Type: research

Zika Virus Vaccine Development: Progress in the Face of New Challenges.
Abstract 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 sa...
Source: Annual Review of Medicine - November 2, 2018 Category: General Medicine Authors: Diamond MS, Ledgerwood JE, Pierson TC Tags: Annu Rev Med Source Type: research

New Hope for Therapeutic Cancer Vaccines in the Era of Immune Checkpoint Modulation.
Abstract 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 ove...
Source: Annual Review of Medicine - October 31, 2018 Category: General Medicine Authors: Curran MA, Glisson BS Tags: Annu Rev Med Source Type: research

CRISPR Correction of Duchenne Muscular Dystrophy.
Abstract 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 insuf...
Source: Annual Review of Medicine - October 31, 2018 Category: General Medicine Authors: Min YL, Bassel-Duby R, Olson EN Tags: Annu Rev Med Source Type: research

Redirected T Cell Cytotoxicity in Cancer Therapy.
Abstract 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 Tcell 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 address...
Source: Annual Review of Medicine - October 31, 2018 Category: General Medicine Authors: Clynes RA, Desjarlais JR Tags: Annu Rev Med Source Type: research

Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders.
Abstract 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 summ...
Source: Annual Review of Medicine - October 26, 2018 Category: General Medicine Authors: Gantois I, Popic J, Khoutorsky A, Sonenberg N Tags: Annu Rev Med Source Type: research

Expanding Therapeutic Opportunities for Hematopoietic Stem Cell Transplantation: T Cell Depletion as a Model for the Targeted Allograft.
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. Expected final online publication date for the Annual Review of Medicine Volume 70 is January 27, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID: 30359171 [PubMed - as supplied by publisher] (Source: Annual Review of Medicine)
Source: Annual Review of Medicine - October 25, 2018 Category: General Medicine Authors: Cho C, Perales MA Tags: Annu Rev Med Source Type: research

Arrhythmogenic Right Ventricular Cardiomyopathy: Progress Toward Personalized Management.
Abstract 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...
Source: Annual Review of Medicine - October 24, 2018 Category: General Medicine Authors: James CA, Calkins H Tags: Annu Rev Med Source Type: research

Current Status of Living Donor Liver Transplantation in the United States.
Abstract 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-...
Source: Annual Review of Medicine - October 24, 2018 Category: General Medicine Authors: Abu-Gazala S, Olthoff KM Tags: Annu Rev Med Source Type: research

Capitalizing on Insights from Human Genetics to Identify Novel Therapeutic Targets for Coronary Artery Disease.
Abstract 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...
Source: Annual Review of Medicine - October 24, 2018 Category: General Medicine Authors: Young EP, Stitziel NO Tags: Annu Rev Med Source Type: research

Emerging Genetic Therapy for Sickle Cell Disease.
Abstract 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 lentivira...
Source: Annual Review of Medicine - October 24, 2018 Category: General Medicine Authors: Orkin SH, Bauer DE Tags: Annu Rev Med Source Type: research

PD-1 Blockade in Early-Stage Lung Cancer.
Abstract 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. Mu...
Source: Annual Review of Medicine - October 24, 2018 Category: General Medicine Authors: Rosner S, Reuss JE, Forde PM Tags: Annu Rev Med Source Type: research

Gastric Cancer Etiology and Management in Asia and the West.
Abstract 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...
Source: Annual Review of Medicine - October 24, 2018 Category: General Medicine Authors: Russo AE, Strong VE Tags: Annu Rev Med Source Type: research

Long-Acting HIV Drugs for Treatment and Prevention.
Abstract 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 preexposure 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...
Source: Annual Review of Medicine - October 24, 2018 Category: General Medicine Authors: Gulick RM, Flexner C Tags: Annu Rev Med Source Type: research

Cystic Fibrosis: Emerging Understanding and Therapies.
Abstract 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 c...
Source: Annual Review of Medicine - October 12, 2018 Category: General Medicine Authors: Rey MM, Bonk MP, Hadjiliadis D Tags: Annu Rev Med Source Type: research

Innovations in Ventricular Assist Devices for End-Stage Heart Failure.
Abstract 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...
Source: Annual Review of Medicine - October 8, 2018 Category: General Medicine Authors: Miller RJH, Teuteberg JJ, Hunt SA Tags: Annu Rev Med Source Type: research

Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors and the Treatment of Type 2 Diabetes.
Abstract 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 remarkab...
Source: Annual Review of Medicine - September 26, 2018 Category: General Medicine Authors: Kramer CK, Zinman B Tags: Annu Rev Med Source Type: research

Active Surveillance as First-Line Management of Papillary Microcarcinoma.
Abstract 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....
Source: Annual Review of Medicine - September 19, 2018 Category: General Medicine Authors: Ito Y, Miyauchi A Tags: Annu Rev Med Source Type: research

New and Emerging Therapies for Pulmonary Arterial Hypertension.
Abstract 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 elucid...
Source: Annual Review of Medicine - September 14, 2018 Category: General Medicine Authors: Spiekerkoetter E, Kawut SM, de Jesus Perez VA Tags: Annu Rev Med Source Type: research

Molecular Diagnostics for Mycobacterium tuberculosis Infection.
Abstract 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 ar...
Source: Annual Review of Medicine - August 20, 2018 Category: General Medicine Authors: Dicks KV, Stout JE Tags: Annu Rev Med Source Type: research