Vaginal bacterial communities are thought to help prevent sexually transmitted infections. Bacterial vaginosis (BV) is a common clinical syndrome in which the protective lactic acid–producing bacteria (mainly species of the Lactobacillus genus) are supplanted by a diverse array of anaerobic bacteria. Epidemiologically, BV has been shown to be an independent risk factor for adverse outcomes including preterm birth, development of pelvic inflammatory disease, and acquisition of sexually transmitted infections. Longitudinal studies of the vaginal microbiome using molecular techniques such as 16S ribosomal DNA analysis may lead to interventions that shift the vaginal microbiota toward more protective states.
Rebecca M. Brotman
Syphilis is a fascinating and perplexing infection, with protean clinical manifestations and both diagnostic and management ambiguities. Treponema pallidum subsp. pallidum, the agent of syphilis, is challenging to study in part because it cannot be cultured or genetically manipulated. Here, we review recent progress in the application of modern molecular techniques to understanding the biological basis of this multistage disease and to the development of new tools for diagnosis, for predicting efficacy of treatment with alternative antibiotics, and for studying the transmission of infection through population networks.
Emily L. Ho, Sheila A. Lukehart
Sexually transmitted infections (STIs) have plagued humans for millennia and can result in chronic disease, pregnancy complications, infertility, and even death. Recent technological advances have led to a better understanding of the causative agents for these infections as well as aspects of their pathogenesis that might represent novel therapeutic targets. The articles in this Review Series provide excellent updates on the recent advances in understanding of the pathogenesis of some very important and persistent STIs and discuss the importance of considering each pathogen in the broader context of the environment of the individual who it infects.
Ischemic kidney injury often occurs in the context of multiple organ failure and sepsis. Here, we review the major components of this dynamic process, which involves hemodynamic alterations, inflammation, and endothelial and epithelial cell injury, followed by repair that can be adaptive and restore epithelial integrity or maladaptive, leading to chronic kidney disease. Better understanding of the cellular pathophysiological processes underlying kidney injury and repair will hopefully result in the design of more targeted therapies to prevent the injury, hasten repair, and minimize chronic progressive kidney disease.
Joseph V. Bonventre, Li Yang
Nearly all stress stimuli (e.g., inflammatory cytokines, glucocorticoids, chemotherapeutics, etc.) induce sphingolipid synthesis, leading to the accumulation of ceramides and ceramide metabolites. While the role of these lipids in the regulation of cell growth and death has been studied extensively, recent studies suggest that a primary consequence of ceramide accumulation is an alteration in metabolism. In both cell-autonomous systems and complex organisms, ceramides modify intracellular signaling pathways to slow anabolism, ensuring that catabolism ensues. These ceramide actions have important implications for diseases associated with obesity, such as diabetes and cardiovascular disease.
Benjamin T. Bikman, Scott A. Summers
Rapid and sophisticated improvements in molecular analysis have allowed us to sequence whole human genomes as well as cancer genomes, and the findings suggest that we may be approaching the ability to individualize the diagnosis and treatment of cancer. This paradigmatic shift in approach will require clinicians and researchers to overcome several challenges including the huge spectrum of tumor types within a given cancer, as well as the cell-to-cell variations observed within tumors. This review discusses how next-generation sequencing of breast cancer genomes already reveals insight into tumor heterogeneity and how it can contribute to future breast cancer classification and management.
Hege G. Russnes, Nicholas Navin, James Hicks, Anne-Lise Borresen-Dale
Many tumors, including breast cancer, are maintained by a subpopulation of cells that display stem cell properties, mediate metastasis, and contribute to treatment resistance. These cancer stem cells (CSCs) are regulated by complex interactions with the components of the tumor microenvironment — including mesenchymal stem cells, adipocytes, tumor associated fibroblasts, endothelial cells, and immune cells — through networks of cytokines and growth factors. Since these components have a direct influence on CSC properties, they represent attractive targets for therapeutic development.
Hasan Korkaya, Suling Liu, Max S. Wicha
Breast cancer, rather than constituting a monolithic entity, comprises heterogeneous tumors with different clinical characteristics, disease courses, and responses to specific treatments. Tumor-intrinsic features, including classical histological and immunopathological classifications as well as more recently described molecular subtypes, separate breast tumors into multiple groups. Tumor-extrinsic features, including microenvironmental configuration, also have prognostic significance and further expand the list of tumor-defining variables. A better understanding of the features underlying heterogeneity, as well as of the mechanisms and consequences of their interactions, is essential to improve targeting of existing therapies and to develop novel agents addressing specific combinations of features.
Nicholas R. Bertos, Morag Park
In recent years the description of well-defined molecular subtypes of breast cancer, together with the identification of the driving genetic alterations and signaling pathways, has led to the clinical development of a number of successful molecular targeted agents. This is best exemplified in the subset of HER2-amplified breast cancers, in which an increasing number of active agents are changing the natural history of this aggressive disease. Other targets are under exploration, and the clinical development of these agents will require a change from the current large, randomized trials in unselected patient populations to smaller trials in groups with a molecularly defined tumor type. In addition, combinatorial approaches that act on the secondary mutations and/or compensatory pathways in resistant tumors may markedly improve on the effects of targeted agents used alone.
Michaela J. Higgins, José Baselga
Breast cancer is a heterogeneous disease. There is a high degree of diversity between and within tumors as well as among cancer-bearing individuals, and all of these factors together determine the risk of disease progression and therapeutic resistance. Advances in technologies such as whole-genome sequencing and functional viability screens now allow us to analyze tumors at unprecedented depths. However, translating this increasing knowledge into clinical practice remains a challenge in part due to tumor evolution driven by the diversity of cancer cell populations and their microenvironment. The articles in this Review series discuss recent advances in our understanding of breast tumor heterogeneity, therapies tailored based on this knowledge, and future ways of assessing and treating heterogeneous tumors.
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