Targeting of the Hedgehog Signaling Pathway in Cancer Treatment

The Hedgehog (Hh) signaling pathway is a developmental pathway that is highly conserved evolutionarily. While typically only displaying high activity during embryogenesis, overactivation of the Hh pathway in adults has been linked to multiple forms of cancer including acute myeloid leukemia, myelofibrosis, basal-cell carcinoma, pancreatic ductal adrenal carcinoma, and triple negative breast cancer. The prevalence of Hh activation in many different cancers has made it a prime target for inhibition of these cancers through novel therapies. This literature review sought to assess the current state of cancer treatment through inhibition of Hh signaling. Most current clinical trials involving the pathway use Smoothened (SMO) antagonists to limit GLI1 production and ultimately inhibit Hh signaling. Currently, the FDA has approved the use of the SMO antagonists vismodegib, sonidegib, and glasdegib for cancer treatment. While only these small molecule inhibitors of Hh signaling have been approved for cancer treatment at this point, inhibition of the Hh signaling has shown to be a promising avenue for novel cancer therapies, particularly for future treatment of basal-cell carcinoma

Differences in intracellular localisation of ANKH mutants that relate to mechanisms of calcium pyrophosphate deposition disease and craniometaphyseal dysplasia

ANKH mutations are associated with calcium pyrophosphate deposition disease and craniometaphyseal dysplasia. This study investigated the effects of these ANKH mutants on cellular localisation and associated biochemistry. We generated four ANKH overexpression-plasmids containing either calcium pyrophosphate deposition disease or craniometaphyseal dysplasia linked mutations: P5L, E490del and S375del, G389R. They were transfected into CH-8 articular chondrocytes and HEK293 cells. The ANKH mutants dynamic differential localisations were imaged and we investigated the interactions with the autophagy marker LC3. Extracellular inorganic pyrophosphate, mineralization, ENPP1 activity expression of ENPP1, TNAP and PIT-1 were measured. P5L delayed cell membrane localisation but once recruited into the membrane it increased extracellular inorganic pyrophosphate, mineralization, and ENPP1 activity. E490del remained mostly cytoplasmic, forming punctate co-localisations with LC3, increased mineralization, ENPP1 and ENPP1 activity with an initial but unsustained increase in TNAP and PIT-1. S375del trended to decrease extracellular inorganic pyrophosphate, increase mineralization. G389R delayed cell membrane localisation, trended to decrease extracellular inorganic pyrophosphate, increased mineralization and co-localised with LC3. Our results demonstrate a link between pathological localisation of ANKH mutants with different degrees in mineralization. Furthermore, mutant ANKH functions are related to synthesis of defective proteins, inorganic pyrophosphate transport, ENPP1 activity and expression of ENPP1, TNAP and PIT-1

Solution-Phase Combinatorial Chemistry in Lead Discovery

Solution-phase approaches in combinatorial chemistry complement solid-phase approaches and each can be used to advantage in particular circumstances. Solution-phase synthesis of pools of compounds, whilst allowing successful identification of a selection of good lead structures for medicinal chemistry programmes, also reinforced a number of the disadvantages of such an approach. Solution-phase parallel synthesis of discrete compounds has, however, proved to be a very useful and popular approach both for lead generation and in lead optimisation work. The range of chemistry suitable for use in such approaches is expanding rapidly and some of these chemistries are discussed. The current focus is on enhancing the quality of compounds prepared in array formats, and we describe a number of useful approaches which are being developed to that end

The Prostate Care Questionnaire for Carers (PCQ-C): reliability, validity and acceptability

<p>Abstract</p> <p>Background</p> <p>Patient experience is commonly monitored in evaluating and improving health care, but the experience of carers (partners/relatives/friends) is rarely monitored even though the role of carers can often be substantial. For carers to fulfil their role it is necessary to address their needs. This paper describes an evaluation of the reliability, validity and acceptability of the PCQ-C, a newly developed instrument designed to measure the experiences of carers of men with prostate cancer.</p> <p>Methods</p> <p>The reliability, acceptability and validity of the PCQ-C were tested through a postal survey and interviews with carers. The PCQ-C was posted to 1087 prostate cancer patients and patients were asked to pass the questionnaire on to their carer. Non-responders received one reminder. To assess test-retest reliability, 210 carers who had responded to the questionnaire were resent it a second time three weeks later. A subsample of nine carers from patients attending one hospital took part in qualitative interviews to assess validity and acceptability of the PCQ-C. Acceptability to service providers was evaluated based on four hospitals' experiences of running a survey using the PCQ-C.</p> <p>Results</p> <p>Questionnaires were returned by 514 carers (47.3%), and the majority of questions showed less than 10% missing data. Across the sections of the questionnaire internal consistency was high (Cronbach's alpha ranging from 0.80 to 0.89), and test-retest stability showed moderate to high stability (intraclass correlation coefficients ranging from 0.52 to 0.83). Interviews of carers indicated that the PCQ-C was valid and acceptable. Feedback from hospitals indicated that they found the questionnaire useful, and highlighted important considerations for its future use as part of quality improvement initiatives.</p> <p>Conclusions</p> <p>The PCQ-C has been found to be acceptable to carers and service providers having been used successfully in hospitals in England. It is ready for use to measure the aspects of care that need to be addressed to improve the quality of prostate cancer care, and for research.</p

The synthesis and characterisation of coordination and hydrogen-bonded networks based on 4-(3,5-dimethyl-1H-pyrazol-4-yl)benzoic acid

The synthesis, structural and thermal characterisation of a number of coordination complexes featuring the N,O-heteroditopic ligand 4-(3,5-dimethyl-1H-pyrazol-4-yl)benzoate, HL are reported. The reaction of H2L with cobalt(II) and nickel(II) nitrates at room temperature in basic DMF/H2O solution gave discrete mononuclear coordination complexes with the general formula {[M(HL)2(H2O)4]·2DMF} (M = Co (1), Ni (2)), whereas the reaction with zinc(II) nitrate gave [Zn(HL)2]∞, 3, a coordination polymer with distorted diamondoid topology and fourfold interpenetration. Coordination about the tetrahedral Zn(II) nodes in 3 are furnished by two pyrazolyl nitrogen atoms and two carboxylate oxygen atoms to give a mixed N2O2 donor set. Isotopological coordination polymers of zinc(II), {[Zn(HL)2]·2CH3OH·H2O}∞, 4, and cobalt(II), [Co(HL)2]∞, 5, are formed when the reactions are carried out under solvothermal conditions in methanol (80 °C) and water (180 °C), respectively. The reaction of H2L with cadmium(II) nitrate at room temperature in methanol gives {[Cd(HL)2(MeOH)2]·1.8MeOH}∞6, a 2-D (4,4)-connected coordination polymer, whereas with copper(II) the formation of green crystals that transform into purple crystals is observed. The metastable green phase [Cu3(HL)4(μ2-SO4)(H2O)3]∞, 7, crystallises with conserved binding domains of the heteroditopic ligand and contains two different metal nodes: a dicopper carboxylate paddle wheel motif, and, a dicopper unit bridged by sulfate ions and coordinated by ligand pyrazolyl nitrogen atoms. The resultant purple phase {[Cu(HL)2]·4CH3OH·H2O}∞, 8, however, has single copper ion nodes coordinated by mixed N2O2 donor sets with trans-square planar geometry and is threefold interpenetrated. The desolvation of 8 was followed by powder X-ray diffraction and single crystal X-ray diffraction which show desolvation induces the transition to a more closely packed structure while the coordination geometry about the copper ions and the network topology is retained. Powder X-ray diffraction and microanalysis were used to characterise the bulk purity of the coordination materials 1-6 and 8. The thermal characteristics of 1-2, 4-6 and 8 were studied by TG-DTA. This led to the curious observation of small exothermic events in networks 4, 6, and 8 that appear to be linked to their decomposition. In addition, the solid state structures of H2L and that of its protonated salt, H2L·HNO3, were also determined and revealed that H2L forms a 2-D hydrogen bonded polymer incorporating helical chains formed through N-HO and O-HN interactions, and that [H3L]NO3 forms a 1-D hydrogen-bonded polymer

Deep resequencing reveals excess rare recent variants consistent with explosive population growth

Accurately determining the distribution of rare variants is an important goal of human genetics, but resequencing of a sample large enough for this purpose has been unfeasible until now. Here, we applied Sanger sequencing of genomic PCR amplicons to resequence the diabetes-associated genes KCNJ11 and HHEX in 13,715 people (10,422 European Americans and 3,293 African Americans) and validated amplicons potentially harbouring rare variants using 454 pyrosequencing. We observed far more variation (expected variant-site count ∼578) than would have been predicted on the basis of earlier surveys, which could only capture the distribution of common variants. By comparison with earlier estimates based on common variants, our model shows a clear genetic signal of accelerating population growth, suggesting that humanity harbours a myriad of rare, deleterious variants, and that disease risk and the burden of disease in contemporary populations may be heavily influenced by the distribution of rare variants

Dual ankyrinG and subpial autoantibodies in a man with well-controlled HIV infection with steroid-responsive meningoencephalitis: A case report

Neuroinvasive infection is the most common cause of meningoencephalitis in people living with human immunodeficiency virus (HIV), but autoimmune etiologies have been reported. We present the case of a 51-year-old man living with HIV infection with steroid-responsive meningoencephalitis whose comprehensive pathogen testing was non-diagnostic. Subsequent tissue-based immunofluorescence with acute-phase cerebrospinal fluid revealed anti-neural antibodies localizing to the axon initial segment (AIS), the node of Ranvier (NoR), and the subpial space. Phage display immunoprecipitation sequencing identified ankyrinG (AnkG) as the leading candidate autoantigen. A synthetic blocking peptide encoding the PhIP-Seq-identified AnkG epitope neutralized CSF IgG binding to the AIS and NoR, thereby confirming a monoepitopic AnkG antibody response. However, subpial immunostaining persisted, indicating the presence of additional autoantibodies. Review of archival tissue-based staining identified candidate AnkG autoantibodies in a 60-year-old woman with metastatic ovarian cancer and seizures that were subsequently validated by cell-based assay. AnkG antibodies were not detected by tissue-based assay and/or PhIP-Seq in control CSF (N = 39), HIV CSF (N = 79), or other suspected and confirmed neuroinflammatory CSF cases (N = 1,236). Therefore, AnkG autoantibodies in CSF are rare but extend the catalog of AIS and NoR autoantibodies associated with neurological autoimmunity

BIOFRAG: A new database for analysing BIOdiversity responses to forest FRAGmentation

Habitat fragmentation studies are producing inconsistent and complex results across which it is nearly impossible to synthesise. Consistent analytical techniques can be applied to primary datasets, if stored in a flexible database that allows simple data retrieval for subsequent analyses. Method: We developed a relational database linking data collected in the field to taxonomic nomenclature, spatial and temporal plot attributes and further environmental variables (e.g. information on biogeographic region. Typical field assessments include measures of biological variables (e.g. presence, abundance, ground cover) of one species or a set of species linked to a set of plots in fragments of a forested landscape. Conclusion: The database currently holds records of 5792 unique species sampled in 52 landscapes in six of eight biogeographic regions: mammals 173, birds 1101, herpetofauna 284, insects 2317, other arthropods: 48, plants 1804, snails 65. Most species are found in one or two landscapes, but some are found in four. Using the huge amount of primary data on biodiversity response to fragmentation becomes increasingly important as anthropogenic pressures from high population growth and land demands are increasing. This database can be queried to extract data for subsequent analyses of the biological response to forest fragmentation with new metrics that can integrate across the components of fragmented landscapes. Meta-analyses of findings based on consistent methods and metrics will be able to generalise over studies allowing inter-comparisons for unified answers. The database can thus help researchers in providing findings for analyses of trade-offs between land use benefits and impacts on biodiversity and to track performance of management for biodiversity conservation in human-modified landscapes.Fil: Pfeifer, Marion. Imperial College London; Reino UnidoFil: Lefebvre, Veronique. Imperial College London; Reino UnidoFil: Gardner, Toby A.. Stockholm Environment Institute; SueciaFil: Arroyo Rodríguez, Víctor. Universidad Nacional Autónoma de México; MéxicoFil: Baeten, Lander. University of Ghent; BélgicaFil: Banks Leite, Cristina. Imperial College London; Reino UnidoFil: Barlow, Jos. Lancaster University; Reino UnidoFil: Betts, Matthew G.. State University of Oregon; Estados UnidosFil: Brunet, Joerg. Swedish University of Agricultural Sciences; SueciaFil: Cerezo Blandón, Alexis Mauricio. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Métodos Cuantitativos y Sistemas de Información; ArgentinaFil: Cisneros, Laura M.. University of Connecticut; Estados UnidosFil: Collard, Stuart. Nature Conservation Society of South Australia; AustraliaFil: D´Cruze, Neil. The World Society for the Protection of Animals; Reino UnidoFil: Da Silva Motta, Catarina. Ministério da Ciência, Tecnologia, Inovações. Instituto Nacional de Pesquisas da Amazônia; BrasilFil: Duguay, Stephanie. Carleton University; CanadáFil: Eggermont, Hilde. University of Ghent; BélgicaFil: Eigenbrod, Félix. University of Southampton; Reino UnidoFil: Hadley, Adam S.. State University of Oregon; Estados UnidosFil: Hanson, Thor R.. No especifíca;Fil: Hawes, Joseph E.. University of East Anglia; Reino UnidoFil: Heartsill Scalley, Tamara. United State Department of Agriculture. Forestry Service; Puerto RicoFil: Klingbeil, Brian T.. University of Connecticut; Estados UnidosFil: Kolb, Annette. Universitat Bremen; AlemaniaFil: Kormann, Urs. Universität Göttingen; AlemaniaFil: Kumar, Sunil. State University of Colorado - Fort Collins; Estados UnidosFil: Lachat, Thibault. Swiss Federal Institute for Forest; SuizaFil: Lakeman Fraser, Poppy. Imperial College London; Reino UnidoFil: Lantschner, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche; ArgentinaFil: Laurance, William F.. James Cook University; AustraliaFil: Leal, Inara R.. Universidade Federal de Pernambuco; BrasilFil: Lens, Luc. University of Ghent; BélgicaFil: Marsh, Charles J.. University of Leeds; Reino UnidoFil: Medina Rangel, Guido F.. Universidad Nacional de Colombia; ColombiaFil: Melles, Stephanie. University of Toronto; CanadáFil: Mezger, Dirk. Field Museum of Natural History; Estados UnidosFil: Oldekop, Johan A.. University of Sheffield; Reino UnidoFil: Overal , Williams L.. Museu Paraense Emílio Goeldi. Departamento de Entomologia; BrasilFil: Owen, Charlotte. Imperial College London; Reino UnidoFil: Peres, Carlos A.. University of East Anglia; Reino UnidoFil: Phalan, Ben. University of Southampton; Reino UnidoFil: Pidgeon, Anna Michle. University of Wisconsin; Estados UnidosFil: Pilia, Oriana. Imperial College London; Reino UnidoFil: Possingham, Hugh P.. Imperial College London; Reino Unido. The University Of Queensland; AustraliaFil: Possingham, Max L.. No especifíca;Fil: Raheem, Dinarzarde C.. Royal Belgian Institute of Natural Sciences; Bélgica. Natural History Museum; Reino UnidoFil: Ribeiro, Danilo B.. Universidade Federal do Mato Grosso do Sul; BrasilFil: Ribeiro Neto, Jose D.. Universidade Federal de Pernambuco; BrasilFil: Robinson, Douglas W.. State University of Oregon; Estados UnidosFil: Robinson, Richard. Manjimup Research Centre; AustraliaFil: Rytwinski, Trina. Carleton University; CanadáFil: Scherber, Christoph. Universität Göttingen; AlemaniaFil: Slade, Eleanor M.. University of Oxford; Reino UnidoFil: Somarriba, Eduardo. Centro Agronómico Tropical de Investigación y Enseñanza; Costa RicaFil: Stouffer, Philip C.. State University of Louisiana; Estados UnidosFil: Struebig, Matthew J.. University of Kent; Reino UnidoFil: Tylianakis, Jason M.. University College London; Estados Unidos. Imperial College London; Reino UnidoFil: Teja, Tscharntke. Universität Göttingen; AlemaniaFil: Tyre, Andrew J.. Universidad de Nebraska - Lincoln; Estados UnidosFil: Urbina Cardona, Jose N.. Pontificia Universidad Javeriana; ColombiaFil: Vasconcelos, Heraldo L.. Universidade Federal de Uberlandia; BrasilFil: Wearn, Oliver. Imperial College London; Reino Unido. The Zoological Society of London; Reino UnidoFil: Wells, Konstans. University of Adelaide; AustraliaFil: Willig, Michael R.. University of Connecticut; Estados UnidosFil: Wood, Eric. University of Wisconsin; Estados UnidosFil: Young, Richard P.. Durrell Wildlife Conservation Trust; Reino UnidoFil: Bradley, Andrew V.. Imperial College London; Reino UnidoFil: Ewers, Robert M.. Imperial College London; Reino Unid

An ecological future for weed science to sustain crop production and the environment. A review

Sustainable strategies for managing weeds are critical to meeting agriculture's potential to feed the world's population while conserving the ecosystems and biodiversity on which we depend. The dominant paradigm of weed management in developed countries is currently founded on the two principal tools of herbicides and tillage to remove weeds. However, evidence of negative environmental impacts from both tools is growing, and herbicide resistance is increasingly prevalent. These challenges emerge from a lack of attention to how weeds interact with and are regulated by the agroecosystem as a whole. Novel technological tools proposed for weed control, such as new herbicides, gene editing, and seed destructors, do not address these systemic challenges and thus are unlikely to provide truly sustainable solutions. Combining multiple tools and techniques in an Integrated Weed Management strategy is a step forward, but many integrated strategies still remain overly reliant on too few tools. In contrast, advances in weed ecology are revealing a wealth of options to manage weedsat the agroecosystem levelthat, rather than aiming to eradicate weeds, act to regulate populations to limit their negative impacts while conserving diversity. Here, we review the current state of knowledge in weed ecology and identify how this can be translated into practical weed management. The major points are the following: (1) the diversity and type of crops, management actions and limiting resources can be manipulated to limit weed competitiveness while promoting weed diversity; (2) in contrast to technological tools, ecological approaches to weed management tend to be synergistic with other agroecosystem functions; and (3) there are many existing practices compatible with this approach that could be integrated into current systems, alongside new options to explore. Overall, this review demonstrates that integrating systems-level ecological thinking into agronomic decision-making offers the best route to achieving sustainable weed management