Recent Molecular Discoveries Research Articles

The impact of recent advances in genetics in understanding disease mechanisms underlying the long QT syndromes.

Long QT syndrome refers to a characteristic abnormality of the electrocardiogram and it is associated with a form of ventricular tachycardia known as torsade-de-pointes and sudden arrhythmic death. It can occur as part of a hereditary syndrome or can be acquired usually because of drug administration. Here we review recent genetic, molecular and cellular discoveries and outline how they have furthered our understanding of this disease. Specifically we focus on compound mutations, genome wide association studies of QT interval, modifier genes and the therapeutic implications of this recent work.

The Basics of Bacteriuria: Strategies of Microbes for Persistence in Urine.

Bacteriuria, the presence of bacteria in urine, is associated with asymptomatic, as well as symptomatic, urinary tract infection (UTI). Bacteriuria underpins some of the dynamics of microbial colonization of the urinary tract, and probably impacts the progression and persistence of infection in some individuals. Recent molecular discoveries in vitro have elucidated how some key bacterial traits can enable organisms to survive and grow in human urine as a means of microbial fitness adaptation for UTI. Several microbial characteristics that confer bacteruric potential have been identified including de novo synthesis of guanine, relative resistance to D-serine, and catabolism of malic acid. Microbial characteristics such as these are increasingly being defined through the use of synthetic human urine (SHU) in vitro as a model to mimic the in vivo environment that bacteria encounter in the bladder. There is considerable variation in the SHU model systems that have been used to study bacteriuria to date, and this influences the utility of these models. In this review, we discuss recent advances in our understanding of bacteruric potential with a focus on the specific mechanisms underlying traits that promote the growth of bacteria in urine. We also review the application of SHU in research studies modeling UTI and discuss the chemical makeup, and benefits and limitations that are encountered in utilizing SHU to study bacterial growth in urine in vitro.

Genomics of adaptation to host-plants in herbivorous insects.

Herbivorous insects represent the most species-rich lineages of metazoans. The high rate of diversification in herbivorous insects is thought to result from their specialization to distinct host-plants, which creates conditions favorable for the build-up of reproductive isolation and speciation. These conditions rely on constraints against the optimal use of a wide range of plant species, as each must constitute a viable food resource, oviposition site and mating site for an insect. Utilization of plants involves many essential traits of herbivorous insects, as they locate and select their hosts, overcome their defenses and acquire nutrients while avoiding intoxication. Although advances in understanding insect-plant molecular interactions have been limited by the complexity of insect traits involved in host use and the lack of genomic resources and functional tools, recent studies at the molecular level, combined with large-scale genomics studies at population and species levels, are revealing the genetic underpinning of plant specialization and adaptive divergence in non-model insect herbivores. Here, we review the recent advances in the genomics of plant adaptation in hemipterans and lepidopterans, two major insect orders, each of which includes a large number of crop pests. We focus on how genomics and post-genomics have improved our understanding of the mechanisms involved in insect-plant interactions by reviewing recent molecular discoveries in sensing, feeding, digesting and detoxifying strategies. We also present the outcomes of large-scale genomics approaches aimed at identifying loci potentially involved in plant adaptation in these insects.

Advances in genetic and epigenetic analyses of gliomas: a neuropathological perspective.

Gliomas, the most common malignant primary brain tumors, are universally fatal once they progress from low-grade into high-grade neoplasms. In recent years, we have accumulated unprecedented data about the genetic and epigenetic abnormalities in gliomas; yet, our appreciation of how these deadly tumors arise is still rudimentary. One of the major deterrents in understanding gliomagenesis is the remarkably complex and heterogeneous molecular composition of gliomas, as well as their ability to change phenotypically as they progress and recur. In the past decade, several monumental studies have begun to define better glioma heterogeneity. Four distinct molecular subgroups have emerged: proneural, classical, mesenchymal, and neural; which have unique gene expression signatures and prognostic significance. Of these, gliomas of the proneural subtype, which encompass most grade II/III diffuse gliomas and secondary glioblastomas and often carry isocitrate dehydrogenase (IDH) mutations, have emerged as a distinct tumor subclass with a notably superior prognosis. Important molecular markers with prognostic relevance, such as mutant IDH1/2, have already been incorporated into clinical neuropathological practice. The recent molecular discoveries in gliomas have also emphasized the intimate link between epigenetics and genetics in gliomagenesis. Several of the novel genetic mutations described are responsible for distinct epigenetic remodeling in gliomas, the mechanisms of which are currently being elucidated. Importantly, these epigenetic and genomic alterations represent new and exciting drug targets for future therapeutic interventions in our continuous fight with this fatal malignancy.

Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer

Four decades ago, angiogenesis was recognized as a therapeutic target for blocking cancer growth. Because of its importance, VEGF has been at the center stage of antiangiogenic therapy. Now, several years after FDA approval of an anti-VEGF antibody as the first antiangiogenic agent, many patients with cancer and ocular neovascularization have benefited from VEGF-targeted therapy; however, this anticancer strategy is challenged by insufficient efficacy, intrinsic refractoriness, and resistance. Here, we examine recent discoveries of new mechanisms underlying angiogenesis, discuss successes and challenges of current antiangiogenic therapy, and highlight emerging antiangiogenic paradigms.

Genetic and Molecular Differences in Prostate Carcinogenesis between African American and Caucasian American Men

Prostate cancer is the most common non-skin cancer and the second leading cause of cancer-related death for men in the United States. Prostate cancer incidence and associated mortality are highest in African American men in comparison to other races. The observed differences in incidence and disease aggressiveness at presentation support a potential role for different pathways of prostate carcinogenesis between African American and Caucasian men. This review focuses on some of the recent molecular biology discoveries, which have been investigated in prostate carcinogenesis and their likely contribution to the known discrepancies across race and ethnicity. Key discussion points include the androgen receptor gene structure and function, genome-wide association studies and epigenetics. The new observations of the ethnic differences of the ERG oncogene, the most common prostate cancer gene, are providing new insights into ERG based stratification of prostate cancers in the context of ethnically diverse patient populations. This rapidly advancing knowledge has the likely potential to benefit clinical practice. Current and future work will improve the ability to sub-type prostate cancers by molecular alterations and lead to targeted therapy against this common malignancy.

Asymptomatic bacteriuria: prevalence rates of causal microorganisms, etiology of infection in different patient populations, and recent advances in molecular detection

Bacteriuria, or the presence of bacteria in urine, is associated with both asymptomatic and symptomatic urinary tract infection and underpins much of the dynamic of microbial colonization of the urinary tract. The prevalence of bacteriuria in dissimilar patient groups such as healthy adults, institutionalized elderly, pregnant women, and immune-compromised patients varies widely. In addition, assessing the importance of 'significant bacteriuria' in infected individuals represents a diagnostic challenge, partly due to various causal microorganisms, and requires careful consideration of the distinct etiologies of bacteriuria in different populations and circumstances. Recent molecular discoveries have revealed how some bacterial traits can enable organisms to grow in human urine, which, as a fitness adaptation, is likely to influence the progression of bacteriuria in some individuals. In this review, we comprehensively analyze currently available data on the prevalence of causal organisms with a focus on asymptomatic bacteriuria in dissimilar populations. We evaluate recent advances in the molecular detection of bacteriuria from a diagnostic viewpoint and briefly discuss the potential benefits and some of the challenges of these approaches. Overall, this review provides an update on the comparative prevalence and etiology of bacteriuria from both microbiological and clinical perspectives.

New treatments for influenza

Influenza has a long history of causing morbidity and mortality in the human population through routine seasonal spread and global pandemics. The high mutation rate of the RNA genome of the influenza virus, combined with assortment of its multiple genomic segments, promote antigenic diversity and new subtypes, allowing the virus to evade vaccines and become resistant to antiviral drugs. There is thus a continuing need for new anti-influenza therapy using novel targets and creative strategies. In this review, we summarize prospective future therapeutic regimens based on recent molecular and genomic discoveries.

North American Clinical Trials Network for the Treatment of Spinal Cord Injury: goals and progress

The North American Clinical Trials Network (NACTN) for the Treatment of Spinal Cord Injury is a consortium of 10 neurosurgery departments, a data management center, and a pharmacological center. The NACTN was established with the goal of bringing recent molecular and cell-based discoveries in neuroprotection and regeneration from the laboratory into clinical trials that optimize meaningful data outcomes and maximum safety to patients. The requirements of planning and executing clinical trials in spinal cord injury (SCI) and the steps that the NACTN has taken to address these requirements are discussed and illustrated in articles in this issue of the Journal of Neurosurgery: Spine. The progress that the NACTN has made in meeting these goals can be summarized as organizing a network of hospitals capable of enrolling a sufficient number of patients for conducting Phase I and II trials; creating a Data Management Center and a database of the natural history of recovery after SCI (at the time of this writing 485 patients were enrolled in the database); creating a database of the incidence and severity of complications that occur during acute and subacute treatment after SCI; developing a Pharmacological Center capable of performing pharmacokinetic and pharmacodynamic studies of therapeutic drugs; completing enrollment of 36 patients in NACTN's first clinical trial, a Phase I study of riluzole, a neuroprotective drug; and performing pharmacokinetic and pharmacodynamic studies of riluzole in acute SCI.

Novel molecular trends in the management of advanced non-small-cell lung cancer

In this article, we will summarize some of the aspects covered by key opinion leaders at the Perspectives in Lung Cancer Congress, particularly focusing on the most recent molecular discoveries in non-small-cell lung cancer which, we believe, will have a deep impact on the clinical development of novel targeted therapies in the future. We discuss genetic alterations in squamous cell carcinoma, crizotinib therapy for ALK-positive tumors, the latest information on antiangiogenic therapies, and strategies aimed at interfering with the Ras–Raf–MEK pathway in more detail. A special emphasis is placed on the potential implications that each covered point will have for the management of advanced non-small-cell lung cancer.

MODY type diabetes: overview and recent findings

We present an update of knowledge on diabetes MODY (maturity onset diabetes of the young), including the recent molecular discoveries, and new diagnostic strategies. Considerable progress has been made in understanding the different molecular abnormalities that cause MODY and the phenotypic consequences resulting therefrom. MODY diabetes is very heterogeneous and is the most common form of monogenic diabetes. Its distribution is worldwide. MODY is an autosomal dominant diabetes mellitus, nonketotic and occurs at an early age (usually before 25 years). To date, at least seven genes are associated with MODY, with frequencies that differ from one population to another. Both 2 and 3 subtypes predominate, while other subtypes (1, 4, 5, 6 and 7) concern only a few families. Since its discovery in the sixties, studies have succeeded to fully clarify the epidemiological, molecular and clinical diagnosis of each subtype, to provide better care for patients. However, the subject of MODY has not yet revealed all its secrets. Indeed, it remains to identify other genes that are associated with MODY X.

Spinal muscular atrophy: diagnosis, treatment and future prospects

To report on recent genetic and molecular discoveries and on future prospects for the treatment of spinal muscular atrophy (SMA), thereby helping healthcare professionals to make a quick diagnosis and provide appropriate and timely therapeutic support. Information was collected from scientific articles published in the last 2 decades, retrieved from the databases SciELO, PubMed, and MEDLINE. SMA is a neurodegenerative disorder with autosomal recessive genetic heredity. It is caused by a homozygous deletion of the survival motor neuron (SMN1) gene. This genetic alteration results in reduced levels of the SMN protein, leading to degeneration of alpha motor neurons of the spinal cord and resulting in muscle weakness and progressive symmetrical proximal paralysis. It is known that basic nutritional and respiratory care and physiotherapy can be important to delaying disease progression and prolonging patients' lives. Several drugs are being tested, some new, others, such as valproic acid, already known; paralysis can be halted, but not reversed. SMA is a difficult to diagnose disorder, because it is little known, and treatment is uncertain. Pharmacological treatments and supportive therapies are not yet able to recover motor neurons or muscle cells that have already been lost, but are aimed at delaying disease progression and improving patients' residual muscle function, as well as offering better quality of life and life expectancy.

Atrofia muscular espinhal: diagnóstico, tratamento e perspectivas futuras

OBJETIVO: Relatar as recentes descobertas geneticas e moleculares, juntamente com as perspectivas futuras, para o tratamento da atrofia muscular espinhal, auxiliando, dessa forma, os profissionais da area da saude a fazerem um rapido diagnostico e proporcionarem um suporte terapeutico correto e precoce. FONTES DOS DADOS: As informacoes foram coletadas a partir de artigos cientificos publicados nas duas ultimas decadas, pesquisados nas bases de dados SciELO, PubMed e MEDLINE. SINTESE DOS DADOS: A atrofia muscular espinhal e uma doenca neurodegenerativa com heranca genetica autossomica recessiva. E causada por uma delecao homozigotica do gene de sobrevivencia do motoneuronio. Essa alteracao genetica resulta na reducao dos niveis da proteina de sobrevivencia do motoneuronio, levando a degeneracao de motoneuronios alfa da medula espinhal, o que resulta em fraqueza e paralisia muscular proximal progressiva simetrica. Sabe-se que alguns cuidados basicos referentes a nutricao, respiracao e fisioterapia podem ser importantes para retardar o progresso da doenca e prolongar a vida dos pacientes. Varios medicamentos estao sendo testados, alguns novos, outros ja conhecidos, como o acido valproico, sendo que a paralisia pode ser estacionada, mas nao revertida. CONCLUSOES: A atrofia muscular espinhal e uma desordem de dificil diagnostico, por ser pouco conhecida, e de tratamento ainda incerto. Os tratamentos farmacologicos e as terapias de suporte existentes ainda nao sao capazes de recuperar os motoneuronios ou as celulas musculares que ja foram perdidos, mas tem o objetivo de retardar o progresso da doenca e melhorar a funcao muscular residual dos pacientes, bem como oferecer uma melhor qualidade e expectativa de vida.

Treatment of patients with colorectal cancer: emphasis on liver metastases

The treatment of colorectal liver metastases has progressed considerably in recent years. Coordinated multidisciplinary management of patients on clinical trials has resulted in 5-year survival rates exceeding 50%, and for certain patients cure is now a realistic goal. For all patients, the approval of six new drugs has contributed to an increase in median survival from 6 months to over 20 months. Recent molecular discoveries promise an era of tailored therapy in which only patients known to benefit will be treated, an approach that will enable more efficient use of the already stretched resources. Clinical trials continue to investigate different combinations and methods of administering approved therapies, but if the progress of the past decade is to be replicated it is imperative that we embrace innovative treatment strategies and novel trial designs. In this review, we highlight the developments that have improved survival for patients with colorectal liver metastases and discuss the many issues that challenge further progress.

Toward a Molecular Classification of Melanoma

The incidence of melanoma is increasing at one of the highest rates of any form of cancer in the United States, with the current lifetime risk being one in 68. At present, there are limited systemic therapies to treat advanced stages of melanoma, and the key to improved survival remains early detection. Recent discoveries have allowed for a clearer picture of the molecular events leading to melanoma development and progression. Since identifying prevalent activating mutations of the BRAF kinase in melanomas, there has been a flood of additional molecular studies to further clarify the role of this pathway and others in melanomagenesis. In particular, recent genetic studies have demonstrated specific genotype-phenotype correlations that provide the first major insights into the molecular subclassification of melanoma and the heterogeneous nature of this malignancy. In this article, we review the most up-to-date molecular discoveries in melanoma biology and provide a framework for understanding their significance in melanoma development and progression. We also provide details on the development of novel therapies based on these recent molecular discoveries and insight into current and planned clinical trials. It is expected that these latest studies in melanoma will help define the critical molecular events involved in disease onset and progression and allow us to move rapidly toward a true molecular classification. We eagerly anticipate rationally designed melanoma therapies based on such a classification scheme and the associated improvements in patient outcomes.

Underlying Cause of Preeclampsia

The underlying cause of preeclampsia has been difficult to identify. Recent cellular and molecular discoveries have determined that women with

Biology of bone and how it orchestrates the form and function of the skeleton.

The principal role of the skeleton is to provide structural support for the body. While the skeleton also serves as the body's mineral reservoir, the mineralized structure is the very basis of posture, opposes muscular contraction resulting in motion, withstands functional load bearing, and protects internal organs. Although the mass and morphology of the skeleton is defined, to some extent, by genetic determinants, it is the tissue's ability to remodel--the local resorption and formation of bone--which is responsible for achieving this intricate balance between competing responsibilities. The aim of this review is to address bone's form-function relationship, beginning with extensive research in the musculoskeletal disciplines, and focusing on several recent cellular and molecular discoveries which help understand the complex interdependence of bone cells, growth factors, physical stimuli, metabolic demands, and structural responsibilities. With a clinical and spine-oriented audience in mind, the principles of bone cell and molecular biology and physiology are presented, and an attempt has been made to incorporate epidemiologic data and therapeutic implications. Bone research remains interdisciplinary by nature, and a deeper understanding of bone biology will ultimately lead to advances in the treatment of diseases and injuries to bone itself.

Keratinocyte adhesion and the missing link: from Dowling–Meara to Hay–WellsSt John's Hospital Dermatological Society Annual Oration 2000

Maintaining a protective barrier against the environment is an essential function of normal skin. Critical to this role are several structural proteins and glycoproteins that contribute to adhesive junctions linking adjacent keratinocytes and basal keratinocytes to the underlying dermis, as well as other regulatory proteins involved in aspects of epidermal development, differentiation and proliferation. Inherited abnormalities in the genes that encode these components may give rise to a range of genodermatoses, many of which are characterized structurally by a 'missing' or perturbed adhesive link and clinically by congenital skin blistering. This oration reviews some of the original clinical descriptions and observations made in this field, as well as providing an update on the corresponding recent molecular discoveries. The emphasis is on contributions made by past and present members of the St John's Hospital Dermatological Society.

Atypical Lymphoproliferative Diseases

Abstract This review addresses the clinical presentation, pathology, and therapy of several uncommon lymphoid proliferations. Because these lymphoproliferations span the characteristics of reactive polymorphous proliferations to clonal malignant neoplasms, they are often difficult to diagnose and treat effectively. In Section I, Dr. Greiner describes the pathology of the spectrum of atypical lymphoid disorders including Castleman's disease, angioimmunoblastic lymphadenopathy, lymphadenopathy in autoimmune diseases, posttransplant lymphoproliferative disorders, and X-linked lymphoproliferative disorder. The relationship to Epstein-Barr virus (EBV) and human herpsesvirus-8 (HHV-8) is discussed, and molecular diagnostic assays and principles for obtaining proper diagnostic evaluation are emphasized. In Section II, Dr. Armitage presents a practical approach to the management of Castleman's disease. The discussion includes the importance of confirmation of the histological diagnosis and careful staging evaluation, therapeutic options, and the increased risks for infection and lymphoma. The appropriate roles of surgical excision, corticosteroids, and combination chemotherapy are addressed along with alternative strategies such as anti-interleukin-6 and bone marrow transplantation. In Section III, Dr. Gross reviews the treatment of EBV-associated lymphoproliferative disorders in primary immunodeficiencies and in post-transplant patients. He gives an update on the recent molecular discoveries in X-linked lymphoproliferative disorder. Preliminary results of a phase II trial of low-dose cyclophosphamide in posttransplant lymphoproliferative disorders and the use of GM-CSF as preemptive therapy are presented.

Atypical Lymphoproliferative Diseases

This review addresses the clinical presentation, pathology, and therapy of several uncommon lymphoid proliferations. Because these lymphoproliferations span the characteristics of reactive polymorphous proliferations to clonal malignant neoplasms, they are often difficult to diagnose and treat effectively.In Section I, Dr. Greiner describes the pathology of the spectrum of atypical lymphoid disorders including Castleman's disease, angioimmunoblastic lymphadenopathy, lymphadenopathy in autoimmune diseases, posttransplant lymphoproliferative disorders, and X-linked lymphoproliferative disorder. The relationship to Epstein-Barr virus (EBV) and human herpsesvirus-8 (HHV-8) is discussed, and molecular diagnostic assays and principles for obtaining proper diagnostic evaluation are emphasized.In Section II, Dr. Armitage presents a practical approach to the management of Castleman's disease. The discussion includes the importance of confirmation of the histological diagnosis and careful staging evaluation, therapeutic options, and the increased risks for infection and lymphoma. The appropriate roles of surgical excision, corticosteroids, and combination chemotherapy are addressed along with alternative strategies such as anti-interleukin-6 and bone marrow transplantation.In Section III, Dr. Gross reviews the treatment of EBV-associated lymphoproliferative disorders in primary immunodeficiencies and in post-transplant patients. He gives an update on the recent molecular discoveries in X-linked lymphoproliferative disorder. Preliminary results of a phase II trial of low-dose cyclophosphamide in posttransplant lymphoproliferative disorders and the use of GM-CSF as preemptive therapy are presented.