[PERSPECTIVES] Tumor-Suppressor Functions of the TP53 Pathway
The fundamental biological importance of the Tp53 gene family is highlighted by its evolutionary conservation for more than one billion years dating back to the earliest multicellular organisms. The TP53 protein provides essential functions in the cellular response to diverse stresses and safeguards maintenance of genomic integrity, and this is manifest in its critical role in tumor suppression. The importance of Tp53 in tumor prevention is exemplified in human cancer where it is the most frequently detected genetic alteration. This is confirmed in animal models, in which a defective Tp53 gene leads inexorably to cancer de...
Source: Cold Spring Harbor perspectives in medicine - May 2, 2016 Category: Research Authors: Aubrey, B. J., Strasser, A., Kelly, G. L. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Inhibition of the Mechanistic Target of Rapamycin (mTOR)-Rapamycin and Beyond
Rapamycin is a Food and Drug Administration (FDA)-approved immunosuppressant and anticancer agent discovered in the soil of Easter Island in the early 1970s. Rapamycin is a potent and selective inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, which acts as a central integrator of nutrient signaling pathways. During the last decade, genetic and pharmaceutical inhibition of mTOR pathway signaling has been found to promote longevity in yeast, worms, flies, and mice. In this article, we will discuss the molecular biology underlying the effects of rapamycin and its physiological effects, evidence for rapa...
Source: Cold Spring Harbor perspectives in medicine - May 2, 2016 Category: Research Authors: Lamming, D. W. Tags: Aging PERSPECTIVES Source Type: research

[PERSPECTIVES] {beta}-Lactam Resistance Mechanisms: Gram-Positive Bacteria and Mycobacterium tuberculosis
The value of the β-lactam antibiotics for the control of bacterial infection has eroded with time. Three Gram-positive human pathogens that were once routinely susceptible to β-lactam chemotherapy—Streptococcus pneumoniae, Enterococcus faecium, and Staphylococcus aureus—now are not. Although a fourth bacterium, the acid-fast (but not Gram-positive-staining) Mycobacterium tuberculosis, has intrinsic resistance to earlier β-lactams, the emergence of strains of this bacterium resistant to virtually all other antibiotics has compelled the evaluation of newer β-lactam combinations as possible con...
Source: Cold Spring Harbor perspectives in medicine - May 2, 2016 Category: Research Authors: Fisher, J. F., Mobashery, S. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] Intergenerational Transfer of Epigenetic Information in Sperm
The inheritance of information beyond DNA sequence, known as epigenetic inheritance, has been implicated in a multitude of biological processes from control of plant flowering time to cancer in humans. In addition to epigenetic inheritance that occurs in dividing cells of a multicellular organism, it is also increasingly clear that at least some epigenetic information is transmitted via the gametes in a multitude of organisms, including mammals. Here, I review the evidence for epigenetic information carriers in mammalian sperm, and explore the emerging field of intergenerational transfer of environmental information. (Sour...
Source: Cold Spring Harbor perspectives in medicine - May 2, 2016 Category: Research Authors: Rando, O. J. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Potassium Channels in Epilepsy
This review attempts to give a concise and up-to-date overview on the role of potassium channels in epilepsies. Their role can be defined from a genetic perspective, focusing on variants and de novo mutations identified in genetic studies or animal models with targeted, specific mutations in genes coding for a member of the large potassium channel family. In these genetic studies, a demonstrated functional link to hyperexcitability often remains elusive. However, their role can also be defined from a functional perspective, based on dynamic, aggravating, or adaptive transcriptional and posttranslational alterations. In the...
Source: Cold Spring Harbor perspectives in medicine - May 2, 2016 Category: Research Authors: Kohling, R., Wolfart, J. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet
Antiseizure drugs (ASDs), also termed antiepileptic drugs, are the main form of symptomatic treatment for people with epilepsy, but not all patients become free of seizures. The ketogenic diet is one treatment option for drug-resistant patients. Both types of therapy exert their clinical effects through interactions with one or more of a diverse set of molecular targets in the brain. ASDs act by modulation of voltage-gated ion channels, including sodium, calcium, and potassium channels; by enhancement of -aminobutyric acid (GABA)-mediated inhibition through effects on GABAA receptors, the GABA transporter 1 (GAT1) GABA upt...
Source: Cold Spring Harbor perspectives in medicine - May 2, 2016 Category: Research Authors: Rogawski, M. A., Loscher, W., Rho, J. M. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[ERRATUM] Erratum: p53 and Medulloblastoma
(Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - April 1, 2016 Category: Research Authors: Ramaswamy, V., Nor, C., Taylor, M. D. Tags: ERRATUM Source Type: research

[PERSPECTIVES] Genetic Modifiers of the p53 Pathway
The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer; this gene is subject to inactivation by mutation or deletion in>50% of sporadic cancers. Genes that encode proteins that regulate p53 function, such as MDM2, MDM4, and CDKN2A (p14ARF) are also frequently altered in tumors, and it is generally believed that the p53 pathway is likely to be inactivated by mutation in close to 100% of human tumors. Unlike most other cancer-relevant signaling pathways, some of the genes in the p53 pathway contain functionally significant single nucleotide polymorphisms (SNPs) that alter the amplitude of signa...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2016 Category: Research Authors: Basu, S., Murphy, M. E. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Autophagy and p53
Macroautophagy (autophagy hereafter) captures, degrades, and recycles intracellular components to maintain metabolic homeostasis and protein and organelle quality control. Autophagy thereby promotes survival in starvation and prevents tissue degeneration. There is an important relationship between autophagy and p53. Autophagy suppresses p53 and also p53 activates autophagy. The suppression of p53 by autophagy is important for tumor promotion and likely also for preventing tissue degeneration. Alternatively, the activation of autophagy by p53 suggests that autophagy is part of the protective function of p53. Uncovering the ...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2016 Category: Research Authors: White, E. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] How Research on Human Progeroid and Antigeroid Syndromes Can Contribute to the Longevity Dividend Initiative
Although translational applications derived from research on basic mechanisms of aging are likely to enhance health spans and life spans for most of us (the longevity dividend), there will remain subsets of individuals with special vulnerabilities. Medical genetics is a discipline that describes such "private" patterns of aging and can reveal underlying mechanisms, many of which support genomic instability as a major mechanism of aging. We review examples of three classes of informative disorders: "segmental progeroid syndromes" (those that appear to accelerate multiple features of aging), "unimoda...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2016 Category: Research Authors: Hisama, F. M., Oshima, J., Martin, G. M. Tags: Aging PERSPECTIVES Source Type: research

[PERSPECTIVES] Tetracycline Antibiotics and Resistance
Tetracyclines possess many properties considered ideal for antibiotic drugs, including activity against Gram-positive and -negative pathogens, proven clinical safety, acceptable tolerability, and the availability of intravenous (IV) and oral formulations for most members of the class. As with all antibiotic classes, the antimicrobial activities of tetracyclines are subject to both class-specific and intrinsic antibiotic-resistance mechanisms. Since the discovery of the first tetracyclines more than 60 years ago, ongoing optimization of the core scaffold has produced tetracyclines in clinical use and development that are ca...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2016 Category: Research Authors: Grossman, T. H. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] The Emergence of Geroscience as an Interdisciplinary Approach to the Enhancement of Health Span and Life Span
Research on the biology of aging has accelerated rapidly in the last two decades. It is now at the point where translation of the findings into useful approaches to improve the health of the elderly population seems possible. In trying to fill that gap, a new field termed geroscience will be articulated here that attempts to identify the biological underpinnings for the age-dependency of most chronic diseases. Herein, I will review the major conceptual issues leading to the formulation of geroscience as a field, as well as give examples of current areas of inquiry in which basic aging biology research could lead to therape...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2016 Category: Research Authors: Sierra, F. Tags: Aging PERSPECTIVES Source Type: research

[PERSPECTIVES] A Molecular Perspective on Procedures and Outcomes with Assisted Reproductive Technologies
The emerging association of assisted reproductive technologies with adverse perinatal outcomes has prompted the in-depth examination of clinical and laboratory protocols and procedures and their possible effects on epigenetic regulatory mechanism(s). The application of various approaches to study epigenetic regulation to problems in reproductive medicine has the potential to identify relative risk indicators for particular conditions, diagnostic biomarkers of disease state, and prognostic indicators of outcome. Moreover, when applied genome-wide, these techniques are likely to find novel pathways of disease pathogenesis an...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2016 Category: Research Authors: Mainigi, M. A., Sapienza, C., Butts, S., Coutifaris, C. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Epilepsy and Autism
Epilepsy and autistic spectrum disorder frequently coexist in the same individual. Electroencephalogram (EEG) epileptiform activity is also present at a substantially higher rate in children with autism than normally developing children. As with epilepsy, there are a multitude of genetic and environmental factors that can result in autistic spectrum disorder. There is growing consensus from both animal and clinical studies that autism is a disorder of aberrant connectivity. As measured with functional magnetic resonance imaging (MRI) and EEG, the brain in autistic spectrum disorder may be under- or overconnected or have a ...
Source: Cold Spring Harbor perspectives in medicine - April 1, 2016 Category: Research Authors: Buckley, A. W., Holmes, G. L. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Resistance Mechanisms and the Future of Bacterial Enoyl-Acyl Carrier Protein Reductase (FabI) Antibiotics
Missense mutations leading to clinical antibiotic resistance are a liability of single-target inhibitors. The enoyl-acyl carrier protein reductase (FabI) inhibitors have one intracellular protein target and drug resistance is increased by the acquisition of single-base-pair mutations that alter drug binding. The spectrum of resistance mechanisms to FabI inhibitors suggests criteria that should be considered during the development of single-target antibiotics that would minimize the impact of missense mutations on their clinical usefulness. These criteria include high-affinity, fast on/off kinetics, few drug contacts with r...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2016 Category: Research Authors: Yao, J., Rock, C. O. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] The Neonatal Salivary Transcriptome
The ability to noninvasively assess the physical and developmental status of a neonate is a goal of modern medicine. In recent years, technological advances have permitted the high-throughput analysis of saliva for thousands of genes, proteins, and metabolites from a single sample source. Saliva is an ideal biofluid to assess health, disease, and development in the newborn. It may be harnessed repeatedly, even in the most vulnerable patients, without risk of harm. Translating novel information about an infant’s global development and risk of disease to the neonatal bedside through the salivary transcriptome has the p...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2016 Category: Research Authors: Maron, J. L. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression
P53 is a transcription factor highly inducible by many stress signals such as DNA damage, oncogene activation, and nutrient deprivation. Cell-cycle arrest and apoptosis are the most prominent outcomes of p53 activation. Many studies showed that p53 cell-cycle and apoptosis functions are important for preventing tumor development. p53 also regulates many cellular processes including metabolism, antioxidant response, and DNA repair. Emerging evidence suggests that these noncanonical p53 activities may also have potent antitumor effects within certain context. This review focuses on the cell-cycle arrest and apoptosis functio...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2016 Category: Research Authors: Chen, J. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Metformin: A Hopeful Promise in Aging Research
Even though the inevitable process of aging by itself cannot be considered a disease, it is directly linked to life span and is the driving force behind all age-related diseases. It is an undisputable fact that age-associated diseases are among the leading causes of death in the world, primarily in industrialized countries. During the last several years, an intensive search of antiaging treatments has led to the discovery of a variety of drugs that promote health span and/or life extension. The biguanide compound metformin is widely used for treating people with type 2 diabetes and appears to show protection against cancer...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2016 Category: Research Authors: Novelle, M. G., Ali, A., Dieguez, C., Bernier, M., de Cabo, R. Tags: Aging PERSPECTIVES Source Type: research

[PERSPECTIVES] Translating the Science of Aging into Therapeutic Interventions
Life and health span have been extended in experimental animals using drugs that are potentially translatable into humans. Considerable effort is needed beyond the usual steps in drug development to devise the models, and realistic preclinical and clinical trial strategies are required to advance these agents into clinical application. It will be important to focus on subjects who already have symptoms or are at imminent risk of developing disorders related to fundamental aging processes, to use short-term, clinically relevant outcomes, as opposed to long-term outcomes, such as health span or life span, and to validate end...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2016 Category: Research Authors: Kirkland, J. L. Tags: Aging PERSPECTIVES Source Type: research

[PERSPECTIVES] Status Epilepticus
Although the majority of seizures are brief and cause no long-term consequences, a subset is sufficiently prolonged that long-term consequences can result. These very prolonged seizures are termed "status epilepticus" (SE) and are considered a neurological emergency. The clinical presentation of SE can be diverse. SE can occur at any age but most commonly occurs in the very young and the very old. There are numerous studies on SE in animals in which the pathophysiology, medication responses, and pathology can be rigorously studied in a controlled fashion. Human data are consistent with the animal data. In particu...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2016 Category: Research Authors: Seinfeld, S., Goodkin, H. P., Shinnar, S. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Channels in Epilepsy
We describe the normal function of HCN channels and discuss how aberrant expression, assembly, trafficking, and posttranslational modifications contribute to experimental and human epilepsy. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - March 1, 2016 Category: Research Authors: Brennan, G. P., Baram, T. Z., Poolos, N. P. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Hepatitis B Virus X and Regulation of Viral Gene Expression
The efficient replication of hepatitis B virus (HBV) requires the HBV regulatory hepatitis B virus X (HBx) protein. The exact contributions of HBx are not fully understood, in part because of the limitations of the assays used for its study. When HBV replication is driven from a plasmid DNA, the contribution of HBx is modest. However, there is an absolute requirement for HBx in assays that recapitulate the infectious virus life cycle. There is much evidence that HBx can contribute directly to HBV replication by acting on viral promoters embedded within protein coding sequences. In addition, HBx may also contribute indirect...
Source: Cold Spring Harbor perspectives in medicine - March 1, 2016 Category: Research Authors: Slagle, B. L., Bouchard, M. J. Tags: The Hepatitis B and Delta Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Effects of Maternal Obesity on Fetal Programming: Molecular Approaches
Maternal obesity has become a worldwide epidemic. Obesity and a high-fat diet have been shown to have deleterious effects on fetal programming, predisposing offspring to adverse cardiometabolic and neurodevelopmental outcomes. Although large epidemiological studies have shown an association between maternal obesity and adverse outcomes for offspring, the underlying mechanisms remain unclear. Molecular approaches have played a key role in elucidating the mechanistic underpinnings of fetal malprogramming in the setting of maternal obesity. These approaches include, among others, characterization of epigenetic modifications, ...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2016 Category: Research Authors: Neri, C., Edlow, A. G. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] p53 and Meduloblastoma
Our understanding of medulloblastoma biology has increased dramatically over the past decade, in part a result of the recognition that there exists tremendous intertumoral heterogeneity not apparent by morphology alone. A particular area that significantly changed our approach to medulloblastoma has been an increased understanding of the role of p53. A role for p53 in medulloblastoma has been established over the past 20 years, however, not until recently has its significance been identified. Recent developments in the understanding of intertumor heterogeneity has clarified the role of TP53 mutations, as the importance of ...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2016 Category: Research Authors: Ramaswamy, V., Nor, C., Taylor, M. D. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Articulating the Case for the Longevity Dividend
The survival of large segments of human populations to advanced ages is a crowning achievement of improvements in public health and medicine. But, in the 21st century, our continued desire to extend life brings forth a unique dilemma. The risk of death from cardiovascular diseases and many forms of cancer have declined, but even if they continue to do so in the future, the resulting health benefits and enhanced longevities are likely to diminish. It is even possible that healthy life expectancy could decline in the future as major fatal diseases wane. The reason is that the longer we live, the greater is the influence of b...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2016 Category: Research Authors: Olshansky, S. J. Tags: Aging PERSPECTIVES Source Type: research

[PERSPECTIVES] Antibacterials Developed to Target a Single Organism: Mechanisms and Frequencies of Reduced Susceptibility to the Novel Anti-Clostridium difficile Compounds Fidaxomicin and LFF571
Clostridium difficile is the most common cause of antibacterial-associated diarrhea. Clear clinical presentation and rapid diagnostics enable targeted therapy for C. difficile infection (CDI) to start quickly. CDI treatment includes metronidazole and vancomycin (VAN). Despite decades of use for CDI, no clinically meaningful resistance to either agent has emerged. Fidaxomicin (FDX), an RNA polymerase inhibitor, is also approved to treat CDI. Mutants with reduced susceptibility to FDX have been selected in vitro by single and multistep methods. Strains with elevated FDX minimum inhibitory concentrations (MICs) were also iden...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2016 Category: Research Authors: Leeds, J. A. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] The Economic Promise of Delayed Aging
Biomedicine has made enormous progress in the last half century in treating common diseases. However, we are becoming victims of our own success. Causes of death strongly associated with biological aging, such as heart disease, cancer, Alzheimer’s disease, and stroke-cluster within individuals as they grow older. These conditions increase frailty and limit the benefits of continued, disease-specific improvements. Here, we show that a "delayed-aging" scenario, modeled on the biological benefits observed in the most promising animal models, could solve this problem of competing risks. The economic value of de...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2016 Category: Research Authors: Goldman, D. Tags: Aging PERSPECTIVES Source Type: research

[PERSPECTIVES] Whole-Exome Sequencing and Whole-Genome Sequencing in Critically Ill Neonates Suspected to Have Single-Gene Disorders
As the ability to identify the contribution of genetic background to human disease continues to advance, there is no discipline of medicine in which this may have a larger impact than in the care of the ill neonate. Newborns with congenital malformations, syndromic conditions, and inherited disorders often undergo an extensive, expensive, and long diagnostic process, often without a final diagnosis resulting in significant health care, societal, and personal costs. Although ethical concerns have been raised about the use of whole-genome sequencing in medical practice, its role in the diagnosis of rare disorders in ill neon...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2016 Category: Research Authors: Smith, L. D., Willig, L. K., Kingsmore, S. F. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] GABAergic Synchronization in Epilepsy
-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the cerebral cortex. GABAergic inhibition enables synchronization of activity in cortical networks, and contributes to generation of variety of brain activity patterns. In relation to epilepsy, GABAergic inhibition has been traditionally viewed as the main mechanism counterbalancing glutamatergic excitation and preventing hypersynchronous neuronal discharges. Indeed, deficits in GABAergic functions most commonly result in a hyperexcitable epileptic state, and many of the currently used antiepileptic drugs act through enhancement of GABAergic functions. Ho...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2016 Category: Research Authors: Khazipov, R. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Immunity and Inflammation in Epilepsy
This review reports the available evidence on the activation of the innate and adaptive branches of the immune system and the related inflammatory processes in epileptic disorders and the putative pathogenic role of inflammatory processes developing in the brain, as indicated by evidence from experimental and clinical research. Indeed, there is increasing knowledge supporting a role of specific inflammatory mediators and immune cells in the generation and recurrence of epileptic seizures, as well as in the associated neuropathology and comorbidities. Major challenges in this field remain: a better understanding of the key ...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2016 Category: Research Authors: Vezzani, A., Lang, B., Aronica, E. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Transmission and Institutional Infection Control of Tuberculosis
Tuberculosis (TB) transmission control in institutions is evolving with increased awareness of the rapid impact of treatment on transmission, the importance of the unsuspected, untreated case of transmission, and the advent of rapid molecular diagnostics. With active case finding based on cough surveillance and rapid drug susceptibility testing, in theory, it is possible to be reasonably sure that no patient enters a facility with undiagnosed TB or drug resistance. Droplet nuclei transmission of TB is reviewed with an emphasis on risk factors relevant to control. Among environmental controls, natural ventilation and upper-...
Source: Cold Spring Harbor perspectives in medicine - February 1, 2016 Category: Research Authors: Nardell, E. A. Tags: Tuberculosis PERSPECTIVES Source Type: research

[PERSPECTIVES] The Companion Dog as a Model for the Longevity Dividend
The companion dog is the most phenotypically diverse species on the planet. This enormous variability between breeds extends not only to morphology and behavior but also to longevity and the disorders that affect dogs. There are remarkable overlaps and similarities between the human and canine species. Dogs closely share our human environment, including its many risk factors, and the veterinary infrastructure to manage health in dogs is second only to the medical infrastructure for humans. Distinct breed-based health profiles, along with their well-developed health record system and high overlap with the human environment,...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2016 Category: Research Authors: Creevy, K. E., Austad, S. N., Hoffman, J. M., ONeill, D. G., Promislow, D. E. L. Tags: Aging PERSPECTIVES Source Type: research

[PERSPECTIVES] p53 as an Effector or Inhibitor of Therapy Response
Although integrity of the p53 signaling pathway in a given tumor was expected to be a critical determinant of response to therapies, most clinical studies failed to link p53 status and treatment outcome. Here, we present two opposite situations: one in which p53 is an essential effector of cure by targeted leukemia therapies and another one in advanced breast cancers in which p53 inactivation is required for the clinical efficacy of dose-dense chemotherapy. If p53 promotes or blocks therapy response, therapies must be tailored on its status in individual tumors. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - January 4, 2016 Category: Research Authors: Ablain, J., Poirot, B., Esnault, C., Lehmann-Che, J., de The, H. Tags: The p53 Protein PERSPECTIVES Source Type: research

[PERSPECTIVES] Fusidic Acid: A Bacterial Elongation Factor Inhibitor for the Oral Treatment of Acute and Chronic Staphylococcal Infections
Fusidic acid is an oral antistaphylococcal antibiotic that has been used in Europe for more than 40 years to treat skin infections as well as chronic bone and joint infections. It is a steroidal antibiotic and the only marketed member of the fusidane class. Fusidic acid inhibits protein synthesis by binding EF-G-GDP, which results in the inhibition of both peptide translocation and ribosome disassembly. It has a novel structure and novel mode of action and, therefore, there is little cross-resistance with other known antibiotics. Many mutations can occur in the FusA gene that codes for EF-G, and some of these mutations can...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2016 Category: Research Authors: Fernandes, P. Tags: Antibiotics and Antibiotic Resistance PERSPECTIVES Source Type: research

[PERSPECTIVES] Dissecting the Mechanisms Underlying Unusually Successful Human Health Span and Life Span
Humans age at different rates and families with exceptional survival provide the opportunity to understand why some people age slower than others. Unique features exhibited by centenarians include a family history of longevity, compression of morbidity with resultant extension of health span, and biomarkers such as low-circulating insulin-like growth factor 1 (IGF-1) and elevated high-density lipoprotein (HDL) cholesterol levels. Given the rarity of the centenarian phenotype, it has not been surprising that the use of discovery methods that relied on common population single nucleotide polymorphisms (SNPs) to unlock the ge...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2016 Category: Research Authors: Milman, S., Barzilai, N. Tags: Aging PERSPECTIVES Source Type: research

[PERSPECTIVES] Noninvasive Antenatal Determination of Fetal Blood Group Using Next-Generation Sequencing
Hemolytic disease of the fetus and newborn (HDFN) is a condition characterized by a decreased lifespan of fetal red blood cells caused by maternally produced allospecific antibodies transferred to the fetus during pregnancy. The antibodies bind to the corresponding blood group antigens on fetal red blood cells and induce hemolysis. Cell-free DNA derived from the conceptus circulates in maternal blood. Using next-generation sequencing (NGS), it can be determined if this cell-free fetal DNA encodes the corresponding blood group antigen that is the target of the maternal allospecific antibodies. This determination carries no ...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2016 Category: Research Authors: Rieneck, K., Clausen, F. B., Dziegiel, M. H. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of Hox Genes in Female Reproductive Tract Development, Adult Function, and Fertility
HOX genes convey positional identity that leads to the proper partitioning and adult identity of the female reproductive track. Abnormalities in reproductive tract development can be caused by HOX gene mutations or altered HOX gene expression. Diethylstilbestrol (DES) and other endocrine disruptors cause Müllerian defects by changing HOX gene expression. HOX genes are also essential regulators of adult endometrial development. Regulated HOXA10 and HOXA11 expression is necessary for endometrial receptivity; decreased HOXA10 or HOXA11 expression leads to decreased implantation rates. Alternation of HOXA10 and HOXA11 exp...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2016 Category: Research Authors: Du, H., Taylor, H. S. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of Calcium Channels in Epilepsy
A central theme in the quest to unravel the genetic basis of epilepsy has been the effort to elucidate the roles played by inherited defects in ion channels. The ubiquitous expression of voltage-gated calcium channels (VGCCs) throughout the central nervous system (CNS), along with their involvement in fundamental processes, such as neuronal excitability and synaptic transmission, has made them attractive candidates. Recent insights provided by the identification of mutations in the P/Q-type calcium channel in humans and rodents with epilepsy and the finding of thalamic T-type calcium channel dysfunction in the absence of s...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2016 Category: Research Authors: Rajakulendran, S., Hanna, M. G. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Neonatal and Infantile Epilepsy: Acquired and Genetic Models
The incidence of seizures and epilepsies is particularly high during the neonatal and infantile periods. We will review selected animal models of early-life epileptic encephalopathies that have addressed the dyscognitive features of frequent interictal spikes, the pathogenesis and treatments of infantile spasms (IS) or Dravet syndrome, disorders with mammalian target of rapamycin (mTOR) dysregulation, and selected early-life epilepsies with genetic defects. Potentially pathogenic mechanisms in these conditions include interneuronopathies in IS or Dravet syndrome and mTOR dysregulation in brain malformations, tuberous scler...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2016 Category: Research Authors: Galanopoulou, A. S., Moshe, S. L. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Origins and Evolution of Hepatitis B Virus and Hepatitis D Virus
Members of the family Hepadnaviridae fall into two subgroups: mammalian and avian. The detection of endogenous avian hepadnavirus DNA integrated into the genomes of zebra finches has revealed a deep evolutionary origin of hepadnaviruses that was not previously recognized, dating back at least 40 million and possibly>80 million years ago. The nonprimate mammalian members of the Hepadnaviridae include the woodchuck hepatitis virus (WHV), the ground squirrel hepatitis virus, and arctic squirrel hepatitis virus, as well as a number of members of the recently described bat hepatitis virus. The identification of hepatitis B v...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2016 Category: Research Authors: Littlejohn, M., Locarnini, S., Yuen, L. Tags: The Hepatitis B and Delta Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Clinical Aspects of Adult Tuberculosis
Tuberculosis (TB) in adults can present in a large number of ways. The lung is the predominant site of TB. Primary pulmonary TB should be distinguished from postprimary pulmonary TB, which is the most frequent TB manifestation in adults (70%–80% cases). Cough is common, although the chest radiograph often raises suspicion of disease. Sputum sampling is a key step in the diagnosis of TB, and invasive procedures such as bronchoscopy may be necessary to achieve adequate samples for diagnosis. Extrapulmonary involvement, which may present many years after exposure, occurs in a variable proportion of cases (20%–45%)...
Source: Cold Spring Harbor perspectives in medicine - January 4, 2016 Category: Research Authors: Loddenkemper, R., Lipman, M., Zumla, A. Tags: Tuberculosis PERSPECTIVES Source Type: research

[PERSPECTIVES] Has the Rate of Human Aging Already Been Modified?
In recent years, three hypotheses have been set forth positing variations on a common question—Has the rate of human aging already been modified? There is no disputing that people now live longer than ever before in history, and considerable variation in duration of life persists as a fundamental attribute of human longevity, but are these events caused by a measurable and verifiable difference in the rate at which people age, or are there other reasons why they occur? In this article, I explore the historical record involving changes in survival and life expectancy at older ages dating back to 1900, and examine what...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2015 Category: Research Authors: Olshansky, S. J. Tags: Aging PERSPECTIVES Source Type: research

[PERSPECTIVES] The Role of the Microenvironmental Niche in Declining Stem-Cell Functions Associated with Biological Aging
This article focuses on new insights gained through the use of heterochronic parabiosis models, in which an old mouse and a young circulatory system are joined. By studying the brains of both young and old mice, researchers are beginning to uncover circulating proneurogenic "youthful" factors and "aging" factors that decrease stem-cell activity and neurogenesis. Ultimately, the identification of factors that influence stem-cell aging may lead to strategies that slow or even reverse age-related decreases in neural-stem-cell (NSC) function and neurogenesis. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - December 1, 2015 Category: Research Authors: DeCarolis, N. A., Kirby, E. D., Wyss-Coray, T., Palmer, T. D. Tags: Aging PERSPECTIVES Source Type: research

[PERSPECTIVES] Potential Uses and Inherent Challenges of Using Genome-Scale Sequencing to Augment Current Newborn Screening
Since newborn screening (NBS) began in the 1960s, technological advances have enabled its expansion to include an increasing number of disorders. Recent developments now make it possible to sequence an infant’s genome relatively quickly and economically. Clinical application of whole-exome and whole-genome sequencing is expanding at a rapid pace but presents many challenges. Its utility in NBS has yet to be demonstrated and its application in the pediatric population requires examination, not only for potential clinical benefits, but also for the unique ethical challenges it presents. (Source: Cold Spring Harbor pers...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2015 Category: Research Authors: Berg, J. S., Powell, C. M. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Molecular Cross-Talk at the Feto-Maternal Interface
Molecular cross-talk at the feto–maternal interface occurs between many different cell types, including uterine leukocytes, extravillous trophoblast cells, and uterine spiral arteries, is essential for the establishment and maintenance of pregnancy. This review concentrates on human pregnancy and examines three main areas in which cross-talk occurs; immune tolerance, regulation of extravillous trophoblast invasion, and remodeling of the uterine spiral arteries. (Source: Cold Spring Harbor perspectives in medicine)
Source: Cold Spring Harbor perspectives in medicine - December 1, 2015 Category: Research Authors: Lash, G. E. Tags: Molecular Approaches to Reproductive and Newborn Medicine PERSPECTIVES Source Type: research

[PERSPECTIVES] Epigenetics and Epilepsy
Epigenetic processes in the brain involve the transfer of information arising from short-lived cellular signals and changes in neuronal activity into lasting effects on gene expression. Key molecular mediators of epigenetics include methylation of DNA, histone modifications, and noncoding RNAs. Emerging findings in animal models and human brain tissue reveal that epilepsy and epileptogenesis are associated with changes to each of these contributors to the epigenome. Understanding and influencing the molecular mechanisms controlling epigenetic change could open new avenues for treatment. DNA methylation, particularly hyperm...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2015 Category: Research Authors: Henshall, D. C., Kobow, K. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] Interneuron Transplantation as a Treatment for Epilepsy
Stem-cell therapy has extraordinary potential to address critical, unmet needs in the treatment of human disease. One particularly promising approach for the treatment of epilepsy is to increase inhibition in areas of the epileptic brain by grafting new inhibitory cortical interneurons. When grafted from embryos, young -aminobutyric acid (GABA)ergic precursors disperse, functionally mature into host brain circuits as local-circuit interneurons, and can stop seizures in both genetic and acquired forms of the disease. These features make interneuron cell transplantation an attractive new approach for the treatment of intract...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2015 Category: Research Authors: Hunt, R. F., Baraban, S. C. Tags: Epilepsy: The Biology of a Spectrum Disorder PERSPECTIVES Source Type: research

[PERSPECTIVES] The Woodchuck, a Nonprimate Model for Immunopathogenesis and Therapeutic Immunomodulation in Chronic Hepatitis B Virus Infection
The woodchuck hepatitis virus (WHV) and its host, the eastern woodchuck, is a very valuable model system for hepatitis B virus infection. Many aspects of WHV replication and pathogenesis resemble acute and chronic hepatitis B infection in patients. Since the establishment of immunological tools, woodchucks were used to develop new therapeutic vaccines and immunomodulatory approaches to treat chronic hepadnaviral infections. Combination therapy of nucleos(t)ide analogs, with prime–boost vaccination and triple therapy, including immunomodulatory strategies by blocking the interaction of the programmed death-1 (PD-1) re...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2015 Category: Research Authors: Roggendorf, M., Kosinska, A. D., Liu, J., Lu, M. Tags: The Hepatitis B and Delta Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Assembly and Release of Hepatitis B Virus
The hepatitis B virus (HBV) core protein is a dynamic and versatile protein that directs many viral processes. During capsid assembly, core protein allosteric changes ensure efficient formation of a stable capsid that assembles while packaging viral RNA–polymerase complex. Reverse transcription of the RNA genome as well as transport of the capsid to multiple cellular compartments are directed by dynamic phosphorylation and structural changes of core protein. Subsequently, interactions of the capsid with the surface proteins and/or host proteins trigger envelopment and release of the viral capsids or the transport to ...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2015 Category: Research Authors: Selzer, L., Zlotnick, A. Tags: The Hepatitis B and Delta Viruses PERSPECTIVES Source Type: research

[PERSPECTIVES] Patentability of Stem Cells in the United States
Until recently, the patentability of stem cells was well established within the judicial and statutory framework in the United States. However, the shifting landscape of patent law, particularly with regard to patent-eligible subject matter under 35 U.S.C. §101, presents new challenges to the patentability of stem cells. In this paper, we discuss the legal precedent that paved the way for stem cell patents, including Diamond v. Chakrabarty and In re Bergy. Additionally, we review recent Supreme Court cases and recent guidance issued by the U.S. Patent and Trademark Office that impose new limitations on patent-eligible...
Source: Cold Spring Harbor perspectives in medicine - December 1, 2015 Category: Research Authors: Fendrick, S. E., Zuhn, D. L. Tags: Intellectual Property in Molecular Medicine PERSPECTIVES Source Type: research