Personalised cancer medicine Jackson, Sarah E.; Chester, John D.
International journal of cancer,
15 July 2015, 2015-Jul-15, 2015-07-15, 20150715, Letnik:
137, Številka:
2
Journal Article
Recenzirano
The evolving field of personalised medicine is playing an increasingly important role in cancer prevention, diagnosis, prognosis and therapeutics. Its importance in clinical management is ...demonstrated by the recent introduction into routine clinical practice of various individualised, molecularly targeted therapies with increased efficacy and/or reduced toxicity. The identification of cancer predisposition genes, such as the BRCA genes in breast cancer, permits screening programmes to identify patients “at‐risk” of developing cancer and helps them make decisions on individual risk‐modification behaviours. Personalised medicine also plays an increasingly important role in cancer treatment. It is increasingly clear that there are molecularly distinct subtypes of various common cancers, with different therapeutic approaches required for each subtype, for example, the use of the monoclonal antibodies (trastuzumab and cetuximab) in HER2‐positive breast cancer and wild‐type KRAS colorectal cancer; tyrosine kinase inhibitors (imatinib, gefitinib, erlotinib and crizotinib) in chronic myeloid leukaemia, gastrointestinal stromal tumours and non‐small‐cell lung cancer and intracellular agents (vemurafenib and olaparib) in metastatic malignant melanoma and ovarian, breast and prostate cancer. The efficacy of various targeted therapies in such disparate tumours suggests that we are entering an era in which treatment decisions will be based on tumour molecular abnormality profile or “signature,” rather than tumour tissue type or anatomical site of origin, improving patient prognosis and quality of life. This mini review focuses on the role of personalised medicine in cancer prevention and treatment as well as its future direction in oncology.
Many drugs have progressed through preclinical and clinical trials and have been available - for years in some cases - before being recalled by the FDA for unanticipated toxicity in humans. One ...reason for such poor translation from drug candidate to successful use is a lack of model systems that accurately recapitulate normal tissue function of human organs and their response to drug compounds. Moreover, tissues in the body do not exist in isolation, but reside in a highly integrated and dynamically interactive environment, in which actions in one tissue can affect other downstream tissues. Few engineered model systems, including the growing variety of organoid and organ-on-a-chip platforms, have so far reflected the interactive nature of the human body. To address this challenge, we have developed an assortment of bioengineered tissue organoids and tissue constructs that are integrated in a closed circulatory perfusion system, facilitating inter-organ responses. We describe a three-tissue organ-on-a-chip system, comprised of liver, heart, and lung, and highlight examples of inter-organ responses to drug administration. We observe drug responses that depend on inter-tissue interaction, illustrating the value of multiple tissue integration for in vitro study of both the efficacy of and side effects associated with candidate drugs.
Stem cells obtained from amniotic fluid show high proliferative capacity in culture and multilineage differentiation potential. Because of the lack of significant immunogenicity and the ability of ...the amniotic fluid‐derived stem (AFS) cells to modulate the inflammatory response, we investigated whether they could augment wound healing in a mouse model of skin regeneration. We used bioprinting technology to treat full‐thickness skin wounds in nu/nu mice. AFS cells and bone marrow‐derived mesenchymal stem cells (MSCs) were resuspended in fibrin‐collagen gel and “printed” over the wound site. At days 0, 7, and 14, AFS cell‐ and MSC‐driven wound closure and re‐epithelialization were significantly greater than closure and re‐epithelialization in wounds treated by fibrin‐collagen gel only. Histological examination showed increased microvessel density and capillary diameters in the AFS cell‐treated wounds compared with the MSC‐treated wounds, whereas the skin treated only with gel showed the lowest amount of microvessels. However, tracking of fluorescently labeled AFS cells and MSCs revealed that the cells remained transiently and did not permanently integrate in the tissue. These observations suggest that the increased wound closure rates and angiogenesis may be due to delivery of secreted trophic factors, rather than direct cell‐cell interactions. Accordingly, we performed proteomic analysis, which showed that AFS cells secreted a number of growth factors at concentrations higher than those of MSCs. In parallel, we showed that AFS cell‐conditioned media induced endothelial cell migration in vitro. Taken together, our results indicate that bioprinting AFS cells could be an effective treatment for large‐scale wounds and burns.
This study investigated whether amniotic fluid‐derived stem (AFS) cells could augment wound healing in a mouse model of skin regeneration. Results indicate that bioprinting AFS cells could be an effective treatment for large‐scale wounds and burns.
This volume considers the way in which the focus on individual rights may constitute an obstacle to ensuring fairness in criminal proceedings. The increasingly cosmopolitan nature of criminal ...justice, forcing legal systems with different institutional forms and practices to interact with each other as they attempt to combat crime beyond national borders, has accentuated the need for systems to seek legitimacy beyond their domestic traditions. Fairness, expressed in terms of the right to a fair trial in provisions such as Article 6 of the European Convention on Human Rights, has emerged across Europe as the principal means of guaranteeing the legitimacy of criminal proceedings. The consequence of this is that criminal procedure doctrines are framed overwhelmingly in 'constitutional' terms - the protection of defence rights is necessary to restrict and legitimate the state's mandate to prosecute crime. Yet there are various problems with relying solely or predominantly on defence rights as a means of ensuring that proceedings are 'fair' or legitimate and these issues are rarely discussed in the academic literature. In this volume, scholars from the disciplines of law, philosophy and sociology challenge various normative assumptions underpinning our understanding of fairness in criminal proceedings.
The magmatic web beneath Hawai'i Wilding, John D; Zhu, Weiqiang; Ross, Zachary E ...
Science (American Association for the Advancement of Science),
2023-Feb-03, 20230203, Letnik:
379, Številka:
6631
Journal Article
Recenzirano
The deep magmatic architecture of the Hawaiian volcanic system is central to understanding the transport of magma from the upper mantle to the individual volcanoes. We leverage advances in earthquake ...monitoring with deep learning algorithms to image the structures underlying a major mantle earthquake swarm of nearly 200,000 events that rapidly accelerated after the 2018 Kīlauea caldera collapse. At depths of 36 to 43 kilometers, we resolve a 15-kilometers-long collection of near-horizontal sheeted structures that we identify as a sill complex. These sills connect to the lower depths of Kīlauea's plumbing by a 25-kilometers-long belt of seismicity. Additionally, a column of seismicity links the sill complex to a shallow décollement near Mauna Loa. These findings implicate the mantle sill complex as a nexus for magma transport beneath Hawai'i and furthermore indicate widespread magmatic connectivity in the volcanic system.
The purpose of this study was to analyze results of adjuvant stereotactic radiosurgery (SRS) targeted at resection cavities of brain metastases without whole-brain irradiation (WBI).
Patients who ...underwent SRS to the tumor bed, deferring WBI after resection of a brain metastasis, were retrospectively identified.
Seventy-two patients with 76 cavities treated from 1998 to 2006 met inclusion criteria. The SRS was delivered to a median marginal dose of 18.6 Gy (range, 15-30 Gy) targeting an average tumor volume of 9.8 cm(3) (range, 0.1-66.8 cm(3)). With a median follow-up of 8.1 months (range, 0.1-80.5 months), 65 patients had follow-up imaging assessable for control analyses. Actuarial local control rates at 6 and 12 months were 88% and 79%, respectively. On univariate analysis, increasing values of conformality indices were the only treatment variables that correlated significantly with improved local control; local control was 100% for the least conformal quartile compared with 63% for the remaining quartiles. Target volume, dose, and number of sessions were not statistically significant.
In this retrospective series, SRS administered to the resection cavity of brain metastases resulted in a 79% local control rate at 12 months. This value compares favorably with historic results with observation alone (54%) and postoperative WBI (80-90%). Given the improved local control seen with less conformal plans, we recommend inclusion of a 2-mm margin around the resection cavity when using this technique.
Acyl carrier protein (ACP) transports the growing fatty acid chain between enzymatic domains of fatty acid synthase (FAS) during biosynthesis. Because FAS enzymes operate on ACP-bound acyl groups, ...ACP must stabilize and transport the growing lipid chain. ACPs have a central role in transporting starting materials and intermediates throughout the fatty acid biosynthetic pathway. The transient nature of ACP-enzyme interactions impose major obstacles to obtaining high-resolution structural information about fatty acid biosynthesis, and a new strategy is required to study protein-protein interactions effectively. Here we describe the application of a mechanism-based probe that allows active site-selective covalent crosslinking of AcpP to FabA, the Escherichia coli ACP and fatty acid 3-hydroxyacyl-ACP dehydratase, respectively. We report the 1.9 Å crystal structure of the crosslinked AcpP-FabA complex as a homodimer in which AcpP exhibits two different conformations, representing probable snapshots of ACP in action: the 4'-phosphopantetheine group of AcpP first binds an arginine-rich groove of FabA, then an AcpP helical conformational change locks AcpP and FabA in place. Residues at the interface of AcpP and FabA are identified and validated by solution nuclear magnetic resonance techniques, including chemical shift perturbations and residual dipolar coupling measurements. These not only support our interpretation of the crystal structures but also provide an animated view of ACP in action during fatty acid dehydration. These techniques, in combination with molecular dynamics simulations, show for the first time that FabA extrudes the sequestered acyl chain from the ACP binding pocket before dehydration by repositioning helix III. Extensive sequence conservation among carrier proteins suggests that the mechanistic insights gleaned from our studies may be broadly applicable to fatty acid, polyketide and non-ribosomal biosynthesis. Here the foundation is laid for defining the dynamic action of carrier-protein activity in primary and secondary metabolism, providing insight into pathways that can have major roles in the treatment of cancer, obesity and infectious disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The early treatment and rapid closure of acute or chronic wounds is essential for normal healing and prevention of hypertrophic scarring. The use of split thickness autografts is often limited by the ...availability of a suitable area of healthy donor skin to harvest. Cellular and non-cellular biological skin-equivalents are commonly used as an alternative treatment option for these patients, however these treatments usually involve multiple surgical procedures and associated with high costs of production and repeated wound treatment. Here we describe a novel design and a proof-of-concept validation of a mobile skin bioprinting system that provides rapid on-site management of extensive wounds. Integrated imaging technology facilitated the precise delivery of either autologous or allogeneic dermal fibroblasts and epidermal keratinocytes directly into an injured area, replicating the layered skin structure. Excisional wounds bioprinted with layered autologous dermal fibroblasts and epidermal keratinocytes in a hydrogel carrier showed rapid wound closure, reduced contraction and accelerated re-epithelialization. These regenerated tissues had a dermal structure and composition similar to healthy skin, with extensive collagen deposition arranged in large, organized fibers, extensive mature vascular formation and proliferating keratinocytes.
f(T) gravity theory offers an alternative context in which to consider gravitational interactions where torsion, rather than curvature, is the mechanism by which gravitation is communicated. We ...investigate the stability of the Kasner solution with several forms of the arbitrary Lagrangian function examined within the f(T) context. This is a Bianchi type–I vacuum solution with anisotropic expansion factors. In the f(T) gravity setting, the solution must conform to a set of conditions in order to continue to be a vacuum solution of the generalized field equations. With this solution in hand, the perturbed field equations are determined for power-law and exponential forms of the f(T) function. We find that the point which describes the Kasner solution is a saddle point which means that the singular solution is unstable. However, we find the de Sitter universe is a late-time attractor. In general relativity, the cosmological constant drives the isotropization of the spacetime while in this setting the extra f(T) contributions now provide this impetus.
NCBI's Conserved Domain Database (CDD) is a resource for the annotation of protein sequences with the location of conserved domain footprints, and functional sites inferred from these footprints. CDD ...includes manually curated domain models that make use of protein 3D structure to refine domain models and provide insights into sequence/structure/function relationships. Manually curated models are organized hierarchically if they describe domain families that are clearly related by common descent. As CDD also imports domain family models from a variety of external sources, it is a partially redundant collection. To simplify protein annotation, redundant models and models describing homologous families are clustered into superfamilies. By default, domain footprints are annotated with the corresponding superfamily designation, on top of which specific annotation may indicate high-confidence assignment of family membership. Pre-computed domain annotation is available for proteins in the Entrez/Protein dataset, and a novel interface, Batch CD-Search, allows the computation and download of annotation for large sets of protein queries. CDD can be accessed via http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml.
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