The coumarin (benzopyran-2-one, or chromen-2-one) ring system, present in natural products (such as the anticoagulant warfarin) that display interesting pharmacological properties, has intrigued ...chemists and medicinal chemists for decades to explore the natural coumarins or synthetic analogs for their applicability as drugs. Many molecules based on the coumarin ring system have been synthesized utilizing innovative synthetic techniques. The diversity oriented synthetic routes have led to interesting derivatives including the furanocoumarins, pyranocoumarins, and coumarin sulfamates (COUMATES), which have been found to be useful in photochemotherapy, antitumor and anti-HIV therapy, and as stimulants for central nervous system, antibacterials, anti-inflammatory, anti-coagulants, and dyes. Of particular interest in breast cancer chemotherapy, some coumarins and their active metabolite 7-hydroxycoumarin analogs have shown sulfatase and aromatase inhibitory activities. Coumarin based selective estrogen receptor modulators (SERMs) and coumarin-estrogen conjugates have also been described as potential antibreast cancer agents. Since breast cancer is the second leading cause of death in American women behind lung cancer, there is a strong impetus to identify potential new drug treatments for breast cancer. Therefore, the objective of this review is to focus on important coumarin analogs with antibreast cancer activities, highlight their mechanisms of action and structure-activity relationships on selected receptors in breast tissues, and the different methods that have been applied in the construction of these pharmacologically important coumarin analogs.
Reversible acetylation mediated by histone deacetylases (HDACs) influences a broad repertoire of physiological processes, many of which are aberrantly controlled in tumor cells. As HDAC inhibition ...prompts tumor cells to enter apoptosis, small‐molecule HDAC inhibitors have been developed as a new class of mechanism‐based anti‐cancer agent, many of which have entered clinical trials. Although the clinical picture is evolving and the precise utility of HDAC inhibitors remains to be determined, it is noteworthy that certain tumor types undergo a favorable response, in particular hematological malignancies. Vorinostat and romidepsin have been approved for treating cutaneous T‐cell lymphoma in patients with progressive, persistent or recurrent disease. Here, we discuss developments in our understanding of molecular events that underlie the anti‐cancer effects of HDAC inhibitors and relate this information to the emerging clinical picture for the application of these inhibitors in the treatment of cancer.
Histone deacetylases (HDAC) have been strongly associated with epigenetics and cancer development and several inhibitors are used in the treatment of certain types of cancers. The January 2012 issue will bring together a series of review articles focussing on the roles of specific histone deacetylases (HDAC) and their inhibitors in immunology and immune‐related diseases. Further background information about these enzymes is available through the accompanying web focus which links to related articles across the Nature Publishing Group.
Scaffolds have been broadly applied within tissue engineering and regenerative medicine to regenerate, replace, or augment diseased or damaged tissue. For a scaffold to perform optimally, several ...design considerations must be addressed, with an eye toward the eventual form, function, and tissue site. The chemical and mechanical properties of the scaffold must be tuned to optimize the interaction with cells and surrounding tissues. For complex tissue engineering, mass transport limitations, vascularization, and host tissue integration are important considerations. As the tissue architecture to be replaced becomes more complex and hierarchical, scaffold design must also match this complexity to recapitulate a functioning tissue. We outline these design constraints and highlight creative and emerging strategies to overcome limitations and modulate scaffold properties for optimal regeneration. We also highlight some of the most advanced strategies that have seen clinical application and discuss the hurdles that must be overcome for clinical use and commercialization of tissue engineering technologies. Finally, we provide a perspective on the future of scaffolds as a functional contributor to advancing tissue engineering and regenerative medicine.
Macrophages reside in the healthy myocardium, participate in ischemic heart disease, and modulate myocardial infarction (MI) healing. Their origin and roles in post-MI remodeling of nonischemic ...remote myocardium, however, remain unclear.
This study investigated the number, origin, phenotype, and function of remote cardiac macrophages residing in the nonischemic myocardium in mice with chronic heart failure after coronary ligation.
Eight weeks post MI, fate mapping and flow cytometry revealed that a 2.9-fold increase in remote macrophages results from both increased local macrophage proliferation and monocyte recruitment. Heart failure produced by extensive MI, through activation of the sympathetic nervous system, expanded medullary and extramedullary hematopoiesis. Circulating Ly6C(high) monocytes rose from 64±5 to 108±9 per microliter of blood (P<0.05). Cardiac monocyte recruitment declined in Ccr2(-/-) mice, reducing macrophage numbers in the failing myocardium. Mechanical strain of primary murine and human macrophage cultures promoted cell cycle entry, suggesting that the increased wall tension in post-MI heart failure stimulates local macrophage proliferation. Strained cells activated the mitogen-activated protein kinase pathway, whereas specific inhibitors of this pathway reduced macrophage proliferation in strained cell cultures and in the failing myocardium (P<0.05). Steady-state cardiac macrophages, monocyte-derived macrophages, and locally sourced macrophages isolated from failing myocardium expressed different genes in a pattern distinct from the M1/M2 macrophage polarization paradigm. In vivo silencing of endothelial cell adhesion molecules curbed post-MI monocyte recruitment to the remote myocardium and preserved ejection fraction (27.4±2.4 versus 19.1±2%; P<0.05).
Myocardial failure is influenced by an altered myeloid cell repertoire.
The Zika virus (ZIKV) outbreak in the Americas and South Pacific poses a significant burden on human health because of ZIKV's neurotropic effects in the course of fetal development. Vaccine ...candidates against ZIKV are coming online, but immunological tools to study anti-ZIKV responses in preclinical models, particularly T cell responses, remain sparse. We deployed RNA nanoparticle technology to create a vaccine candidate that elicited ZIKV E protein-specific IgG responses in C57BL/6 mice as assayed by ELISA. Using this tool, we identified a unique H-2D
-restricted epitope to which there was a CD8
T cell response in mice immunized with our modified dendrimer-based RNA nanoparticle vaccine. These results demonstrate that this approach can be used to evaluate new candidate antigens and identify immune correlates without the use of live virus.
Vaccines have had broad medical impact, but existing vaccine technologies and production methods are limited in their ability to respond rapidly to evolving and emerging pathogens, or sudden ...outbreaks. Here, we develop a rapid-response, fully synthetic, singledose, adjuvant-free dendrimer nanoparticle vaccine platform wherein antigens are encoded by encapsulated mRNA replicons. To our knowledge, this system is the first capable of generating protective immunity against a broad spectrum of lethal pathogen challenges, including H1N1 influenza, Toxoplasma gondii, and Ebola virus. The vaccine can be formed with multiple antigenexpressing replicons, and is capable of eliciting both CD8⁺ T-cell and antibody responses. The ability to generate viable, contaminant-free vaccines within days, to single or multiple antigens, may have broad utility for a range of diseases.
Increasing demand for global health education in medical training has driven the growth of educational programs predicated on a model of short-term medical service abroad. Almost two-thirds of ...matriculating medical students expect to participate in a global health experience during medical school, continuing into residency and early careers. Despite positive intent, such short-term experiences in global health (STEGHs) may exacerbate global health inequities and even cause harm. Growing out of the "medical missions" tradition, contemporary participation continues to evolve. Ethical concerns and other disciplinary approaches, such as public health and anthropology, can be incorpo rated to increase effectiveness and sustainability, and to shift the culture of STEGHs from focusing on trainees and their home institutions to also considering benefits in host communities and nurtur ing partnerships. The authors propose four core principles to guide ethical development of educational STEGHs: (1) skills building in cross-cultural effective ness and cultural humility, (2) bidirectional participatory relationships, (3) local capacity building, and (4) long-term sustainability. Application of these principles highlights the need for assessment of STEGHs: data collection that allows transparent compar isons, standards of quality, bidirectionality of agreements, defined curricula, and ethics that meet both host and sending countries' standards and needs. To capture the enormous potential of STEGHs, a paradigm shift in the culture of STEGHs is needed to ensure that these experiences balance training level, personal competencies, medical and cross-cultural ethics, and educational objectives to minimize harm and maximize benefits for all involved.
A number of constitutively activated signaling pathways play critical roles in the survival and growth of primary effusion lymphoma cells (PELs) including NFkB and PI3/AKT kinase cascades. NFkBis ...constitutively activated in a number of malignancies, including multiple myeloma, Burkitt's lymphoma and diffuse large cell B-cell lymphoma. However, its role in primary effusion lymphoma has not been fully explored.
We used pharmacological inhibition and gene silencing to define the role of NFkB in growth and survival of PEL cells. Inhibition of NFkB activity by Bay11-7085 resulted in decreased expression of p65 in the nuclear compartment as detected by EMSA assays. In addition, Bay11-7085 treatment caused de-phosphorylation of AKT and its downstream targets suggesting a cross-talk between NFkB and the PI3-kinase/AKT pathway. Importantly, treatment of PEL cells with Bay11-7085 led to inhibition of cell viability and induced apoptosis in a dose dependent manner. Similar apoptotic effects were found when p65 was knocked down using specific small interference RNA. Finally, co-treatment of PEL cells with suboptimal doses of Bay11-7085 and LY294002 led to synergistic apoptotic responses in PEL cells.
These data support a strong biological-link between NFkB and the PI3-kinase/AKT pathway in the modulation of anti-apoptotic effects in PEL cells. Synergistic targeting of these pathways using NFKB- and PI3-kinase/AKT-inhibitors may have a therapeutic potential for the treatment of PEL and possibly other malignancies with constitutive activation of these pathways.
In academic medicine, the attrition of the physician-scientist workforce has been significantly discussed for the past three decades, with substantial attention and funding targeted to stop this ...attrition and attempt to reinvigorate the workforce. Despite these concerns and efforts, the attrition has not been stopped or even significantly slowed, and thus a further understanding of the physician-scientist workforce is needed with a closer look at how this workforce is measured and quantified. Through reviewing three methods by which physician-scientists are identified and understood, limitations in these definitions arise, leading to the basic question: Who qualifies to be a physician-scientist? Answering this question may lead to developing more comprehensive and less restrictive approaches when qualifying and measuring the physician-scientist workforce and appreciating the varying contributions physicians make to research. Through suggesting an expanded appreciation of these research contributions, recognition of collaboration, and funding models that support both of these aspects, the authors hope to add to the conversation by challenging traditional approaches and encouraging movement toward forward-looking definitions that encourage and promote all physicians to engage with research. This reimagining of physician-scientists will result not just in a remeasuring of the workforce but, subsequently, in strengthening the clinical and translational research continuum as well.
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