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1.
Proc Biol Sci ; 291(2028): 20240756, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39137889

RESUMO

Constraint is a fundamental concept in evolutionary theory. Morphology and ecology both are limited by functional, historical and developmental factors to a subset of the theoretical range species could occupy. Cat-like carnivorans (Feliformia) offer a unique opportunity to investigate phenotypic constraint, as several feliform clades are purported to be limited to generalized ecomorphological roles, while others possess extremely specialized durophagous (bone-crushing) and sabretooth morphology. We investigated the evolutionary history of feliforms by considering their phylogeny, morphological disparity and rates of evolution. We recover results that show a mosaic pattern exists in the degree of morphological disparity per anatomical region per clade and ecology. Non-hypercarnivores, such as viverrids (civets and genets), Malagasy euplerids and lophocyonids (extinct hypocarnivores), have the greatest dental disparity, while hypercarnivores (felids, nimravids, many hyaenids) have the lowest dental disparity but highest cranial and mandibular disparity (excluding dentition). However, high disparity is not necessarily associated with high rates of evolution, but instead with ecological radiations. We reveal that relationships between specialization and disparity are not as simple as past research has concluded. Instead, morphological disparity results from an anatomical mosaic of evolution, where different ecologies correlate with and likely channel unique patterns/combinations of disparity per anatomical partition.


Assuntos
Evolução Biológica , Filogenia , Animais , Crânio/anatomia & histologia , Fósseis/anatomia & histologia
2.
New Phytol ; 242(6): 2411-2429, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38659154

RESUMO

Bryophytes, including the lineages of mosses, liverworts, and hornworts, are the second-largest photoautotroph group on Earth. Recent work across terrestrial ecosystems has highlighted how bryophytes retain and control water, fix substantial amounts of carbon (C), and contribute to nitrogen (N) cycles in forests (boreal, temperate, and tropical), tundra, peatlands, grasslands, and deserts. Understanding how changing climate affects bryophyte contributions to global cycles in different ecosystems is of primary importance. However, because of their small physical size, bryophytes have been largely ignored in research on water, C, and N cycles at global scales. Here, we review the literature on how bryophytes influence global biogeochemical cycles, and we highlight that while some aspects of global change represent critical tipping points for survival, bryophytes may also buffer many ecosystems from change due to their capacity for water, C, and N uptake and storage. However, as the thresholds of resistance of bryophytes to temperature and precipitation regime changes are mostly unknown, it is challenging to predict how long this buffering capacity will remain functional. Furthermore, as ecosystems shift their global distribution in response to changing climate, the size of different bryophyte-influenced biomes will change, resulting in shifts in the magnitude of bryophyte impacts on global ecosystem functions.


Assuntos
Briófitas , Mudança Climática , Ciclo do Nitrogênio , Água , Briófitas/fisiologia , Água/metabolismo , Ciclo do Carbono , Carbono/metabolismo , Nitrogênio/metabolismo , Ecossistema
3.
BMC Med Educ ; 24(1): 474, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38689267

RESUMO

BACKGROUND: Belonging is critical for the development and wellbeing of medical students. Belonging, particularly within a 'relational being' paradigm, presents a significant challenge for students, especially within clinical learning environments. Co-creation is a learning relationship in which students are actively involved in the education process. It is inherently relational and promotes belonging within higher education environments. Little is known about utilising co-creation in the curriculum, within medical education. The aim of this study was to explore medical students' experience of co-creation of learning resources within the clinical learning environment. METHODS: Following ethical approval, medical students were invited to become co-creators of a learning bulletin resource, within the paediatric acute receiving unit, at a paediatric teaching hospital. Interpretative phenomenological analysis (IPA) was used to enable an in-depth exploration of how medical students experienced co-creation within the clinical learning environment. Medical students participated in semi-structured interviews about their experience, which were transcribed verbatim and analysed using IPA. The analysis integrated individual lived experiences into an analytic summary. RESULTS: Nine medical students participated. Three group experiential themes were identified: identity maturation; learning community and workplace integration. The support found within this co-created learning community, along with maturation of their identity, allowed the participants to experience a challenge to their existing worldview. This shift in perspective resulted in them responding and behaving in the workplace in new ways, which enabled them to belong as themselves in the clinical learning environment. These findings were situated within the developmental concept of self-authorship, as well as contributing to a new understanding of how co-creation promoted social integration. CONCLUSIONS: Co-creation enabled students to learn in a meaningful way. The relational power of co-creation, can be harnessed to deliver participatory learning experiences, within our increasingly complex healthcare environment, to support the learning, development and integration of doctors of the future.


Assuntos
Estudantes de Medicina , Humanos , Estudantes de Medicina/psicologia , Feminino , Masculino , Educação de Graduação em Medicina , Currículo , Pesquisa Qualitativa , Aprendizagem
4.
Artigo em Inglês | MEDLINE | ID: mdl-39004448

RESUMO

Belonging is critical for the development and well-being of medical students. Feeling a sense of belonging is a significant challenge for medical students within the melee of modern clinical environments. Co-creation is a learning relationship in which students are actively involved in the education process. It is inherently relational and promotes belonging within higher education environments. Little is known about using co-creation in the clinical learning environment, within medical education, or how medical students experience this type of learning structure. This article presents an example of using co-creation during paediatric placement and its evaluation. It then gives practical advice for using co-creation within the reader's own practice, as a paediatric clinician and teacher.

5.
Proc Biol Sci ; 290(1992): 20221062, 2023 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-36722085

RESUMO

Mammalian omnivores are a broad group of species that are often treated uniformly in ecological studies. Here, we incorporate omnivorous dietary differences to investigate previously found mammalian macroevolutionary and macroecological trends. We investigate the frequency with which vertebrate prey, invertebrate prey, fibrous plant material and non-fibrous plant material co-occur in the diets of terrestrial mammals. We quantify the body size distributions and phylogenetic signal of different omnivorous diets and use multistate reversible jump Markov chain Monte Carlo methods to assess the transition rates between diets on the mammalian phylogenetic tree. We find omnivores that consume all four food types are relatively rare, as most omnivores consume only invertebrate prey and non-fibrous plants. In addition, omnivores that only consume invertebrate prey, many of which are from Rodentia, are on average smaller than omnivores that incorporate vertebrate prey. Our transition models have high rates from invertivorous omnivory to herbivory, and from vertivory to prey mixing and ultimately invertivory. We suggest prey type is an important aspect of omnivore macroevolution and macroecology, as it is correlated with body mass, evolutionary history and diet-related evolutionary transition rates. Future work should avoid lumping omnivores into one category given the ecological variety of omnivore diets and their strong evolutionary influence.


Assuntos
Dieta , Mamíferos , Animais , Filogenia , Tamanho Corporal
6.
J Am Chem Soc ; 141(1): 352-362, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30525567

RESUMO

In this work a photosubstitution strategy is presented that can be used for the isolation of chiral organometallic complexes. A series of five cyclometalated complexes Ru(phbpy)(N-N)(DMSO-κS)](PF6) ([1]PF6-[5]PF6) were synthesized and characterized, where Hphbpy = 6'-phenyl-2,2'-bipyridyl, and N-N = bpy (2,2'-bipyridine), phen (1,10-phenanthroline), dpq (pyrazino[2,3- f][1,10]phenanthroline), dppz (dipyrido[3,2- a:2',3'- c]phenazine, or dppn (benzo[ i]dipyrido[3,2- a,2',3'- c]phenazine), respectively. Due to the asymmetry of the cyclometalated phbpy- ligand, the corresponding [Ru(phbpy)(N-N)(DMSO-κS)]+complexes are chiral. The exceptional thermal inertness of the Ru-S bond made chiral resolution of these complexes by thermal ligand exchange impossible. However, photosubstitution by visible light irradiation in acetonitrile was possible for three of the five complexes ([1]PF6-[3]PF6). Further thermal coordination of the chiral sulfoxide ( R)-methyl p-tolylsulfoxide to the photoproduct [Ru(phbpy)(phen)(NCMe)]PF6, followed by reverse phase HPLC, led to the separation and characterization of the two diastereoisomers of [Ru(phbpy)(phen)(MeSO(C7H7))]PF6, thus providing a new photochemical approach toward the synthesis of chiral cyclometalated ruthenium(II) complexes. Full photochemical, electrochemical, and frontier orbital characterization of the cyclometalated complexes [1]PF6-[5]PF6 was performed to explain why [4]PF6 and [5]PF6 are photochemically inert while [1]PF6-[3]PF6 perform selective photosubstitution.

7.
Chemistry ; 25(5): 1260-1268, 2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30318782

RESUMO

Cyclometallated ruthenium complexes typically exhibit red-shifted absorption bands and lower photolability compared to their polypyridyl analogues. They also have lower symmetry, which sometimes makes their synthesis challenging. In this work, the coordination of four N,S bidentate ligands, 3-(methylthio)propylamine (mtpa), 2-(methylthio)ethylamine (mtea), 2-(methylthio)ethyl-2-pyridine (mtep), and 2-(methylthio)methylpyridine (mtmp), to the cyclometallated precursor [Ru(bpy)(phpy)(CH3 CN)2 ]+ (bpy=2,2'-bipyridine, Hphpy=2-phenylpyridine) has been investigated, furnishing the corresponding heteroleptic complexes [Ru(bpy)(phpy)(N,S)]PF6 ([2]PF6 -[5]PF6 , respectively). The stereoselectivity of the synthesis strongly depended on the size of the ring formed by the Ru-coordinated N,S ligand, with [2]PF6 and [4]PF6 being formed stereoselectively, but [3]PF6 and [5]PF6 being obtained as mixtures of inseparable isomers. The exact stereochemistry of the air-stable complex [4]PF6 was established by a combination of DFT, 2D NMR, and single-crystal X-ray crystallographic studies. Finally, [4]PF6 was found to be photosubstitutionally active under irradiation with green light in acetonitrile, which makes it the first cyclometallated ruthenium complex capable of undergoing selective photosubstitution of a bidentate ligand.

8.
Angew Chem Int Ed Engl ; 58(28): 9378-9382, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31046177

RESUMO

Four-way junctions (4WJs) are supramolecular DNA assemblies comprising four interacting DNA strands that in biology are involved in DNA-damage repair. In this study, a new mononuclear platinum(II) complex 1 was prepared that is capable of driving the crystallization of the DNA oligomer 5'-d(CGTACG)-3' specifically into a 4WJ-like motif. In the crystal structure of the 1-CGTACG adduct, the distorted-square-planar platinum complex binds to the core of the 4WJ-like motif through π-π stacking and hydrogen bonding, without forming any platinum-nitrogen coordination bonds. Our observations suggest that the specific molecular properties of the metal complex are crucially responsible for triggering the selective assembly of this peculiar DNA superstructure.


Assuntos
DNA/química , Platina/química , Humanos , Modelos Moleculares , Conformação de Ácido Nucleico
9.
J Am Chem Soc ; 139(14): 4991-4994, 2017 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-28345936

RESUMO

Co-registered molecular logic gates combine two different inputs and outputs, such as light and matter. We introduce a biocompatible CO-releasing molecule (CORM, A) as Mn(I) tricarbonyl complex with the ligand 5-(dimethylamino)-N, N-bis(pyridin-2-ylmethyl) naphthalene-1-sulfonamide (L). CO release is chaperoned by turn-on fluorescence and can be triggered by light (405 nm) as well as with hydrogen peroxide in aqueous phosphate buffer. Complex A behaves as a logic "OR" gate via co-registering the inputs of irradiation (light) and peroxide (matter) into the concomitant outputs fluorescence (light) and CO (matter). Cell viability assays confirm the low toxicity of A toward different human cell lines. The CORM has been used to track the inclusion of A into cancer cells.

10.
Angew Chem Int Ed Engl ; 56(38): 11549-11553, 2017 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-28666065

RESUMO

We describe two water-soluble ruthenium complexes, [1]Cl2 and [2]Cl2 , that photodissociate to release a cytotoxic nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with a low dose (21 J cm-2 ) of red light in an oxygen-independent manner. Using a specific NAMPT activity assay, up to an 18-fold increase in inhibition potency was measured upon red-light activation of [2]Cl2 , while [1]Cl2 was thermally unstable. For the first time, the dark and red-light-induced cytotoxicity of these photocaged compounds could be tested under hypoxia (1 % O2 ). In skin (A431) and lung (A549) cancer cells, a 3- to 4-fold increase in cytotoxicity was found upon red-light irradiation for [2]Cl2 , whether the cells were cultured and irradiated with 1 % or 21 % O2 . These results demonstrate the potential of photoactivated chemotherapy for hypoxic cancer cells, in which classical photodynamic therapy, which relies on oxygen activation, is poorly efficient.


Assuntos
Antineoplásicos/farmacologia , Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Luz , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Humanos , Hipóxia , Nicotinamida Fosforribosiltransferase/metabolismo , Compostos Organometálicos/química , Processos Fotoquímicos , Fotoquimioterapia , Rutênio/química , Relação Estrutura-Atividade
11.
Small ; 12(40): 5579-5590, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27571308

RESUMO

Light upconversion is a very powerful tool in bioimaging as it can eliminate autofluorescence, increase imaging contrast, reduce irradiation damage, and increase excitation penetration depth in vivo. In particular, triplet-triplet annihilation upconverting (TTA-UC) nanoparticles and liposomes offer high upconversion efficiency at low excitation power. However, TTA-UC is quenched in air by oxygen, which also leads to the formation of toxic singlet oxygen. In this work, polyisobutylene-monomethyl polyethylene glycol block copolymers are synthesized and used for preparing polymersomes that upconvert red light into blue light in absence of oxygen. In addition, it is demonstrated that biocompatible antioxidants such as l-ascorbate, glutathionate, l-histidine, sulfite, trolox, or even opti-MEM medium, can be used to protect the TTA-UC process in these polymersomes resulting in red-to-blue upconversion under aerobic conditions. Most importantly, this approach is also functional in living cells. When A549 lung carcinoma cells are treated with TTA-UC polymersomes in the presence of 5 × 10-3 m ascorbate and glutathionate, upconversion in the living cells is one order of magnitude brighter than that observed without antioxidants. These results propose a simple chemical solution to the issue of oxygen sensitivity of TTA-UC, which is of paramount importance for the technological advancement of this technique in biology.


Assuntos
Antioxidantes/farmacologia , Materiais Biocompatíveis/farmacologia , Imageamento Tridimensional , Neoplasias/patologia , Polímeros/química , Células A549 , Linhagem Celular Tumoral , Sequestradores de Radicais Livres/química , Humanos , Hidrodinâmica , Oxigênio/química , Tamanho da Partícula , Fármacos Fotossensibilizantes/química , Solubilidade , Espectrometria de Fluorescência , Eletricidade Estática , Água/química
12.
Chemistry ; 22(51): 18484-18491, 2016 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-27859843

RESUMO

Light-activated ruthenium polypyridyl anticancer prodrugs often suffer from poor water solubility, poor selectivity, and/or ill-defined intracellular targets. Coordination of the d- or l-glucose thioether ligand 3 (2-(2-(2-(methylthio)ethoxy)ethoxy)ethyl-ß-glucopyranoside) to the highly lipophilic ruthenium complex [Ru(tpy)(dppn)(H2 O)]2+ ([1]2+ ; dppn=benzo[i]dipyrido-[3,2-a:2',3'-c]phenazine, tpy=2,2':6',2''-terpyridine) solved all these problems at once. The two enantiomers of [Ru(tpy)(dppn)(3)][PF6 ]2 , [d-2][PF6 ]2 and [l-2][PF6 ]2 , were soluble in water, which allowed the influence of the chirality of the glucose moiety on uptake, toxicity, and intracellular localization of the prodrug to be probed without changing any other physicochemical properties. Both compounds showed mild, but different, cytotoxicity in A549 (human lung carcinoma) and MCF-7 (human breast adenocarcinoma) cancer cells in the dark, whereas following low doses of visible light irradiation (3.1 J cm-2 at λ = 454 nm), a similar, but high cytotoxicity (EC50 < 1 µm), was observed. Irrespective of the chirality, both slightly emissive Ru complexes were found in the mitochondria, and two modes of action may contribute to light-induced cell death: 1) the glucose thioether ligand is photosubstituted by water, thus [1]2+ , which interacts with DNA at an exceptionally high 400:1 base pair/Ru ratio, is released; 2) both [1]2+ and [2]2+ produce massive amounts of singlet oxygen, which leads to very efficient photodynamic DNA cleavage.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/química , Clivagem do DNA/efeitos dos fármacos , Glucose/química , Mitocôndrias/química , Mitocôndrias/efeitos dos fármacos , Pró-Fármacos/química , Rutênio/química , Oxigênio Singlete/química , Antineoplásicos/química , Ligantes
13.
Chemistry ; 22(31): 10960-8, 2016 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-27373895

RESUMO

The crystal structure and in vitro cytotoxicity of the amphiphilic ruthenium complex [3](PF6 )2 are reported. Complex [3](PF6 )2 contains a Ru-S bond that is stable in the dark in cell-growing medium, but is photosensitive. Upon blue-light irradiation, complex [3](PF6 )2 releases the cholesterol-thioether ligand 2 and an aqua ruthenium complex [1](PF6 )2 . Although ligand 2 and complex [1](PF6 )2 are by themselves not cytotoxic, complex [3](PF6 )2 was unexpectedly found to be as cytotoxic as cisplatin in the dark, that is, with micromolar effective concentrations (EC50 ), against six human cancer cell lines (A375, A431, A549, MCF-7, MDA-MB-231, and U87MG). Blue-light irradiation (λ=450 nm, 6.3 J cm(-2) ) had little influence on the cytotoxicity of [3](PF6 )2 after 6 h of incubation time, but it increased the cytotoxicity of the complex by a factor 2 after longer (24 h) incubation. Exploring the unexpected biological activity of [3](PF6 )2 in the dark elucidated an as-yet unknown bifaceted mode of action that depended on concentration, and thus, on the aggregation state of the compound. At low concentration, it acts as a monomer, inserts into the membrane, and can deliver [1](2+) inside the cell upon blue-light activation. At higher concentrations (>3-5 µm), complex [3](PF6 )2 forms supramolecular aggregates that induce non-apoptotic cell death by permeabilizing cell membranes and extracting lipids and membrane proteins.


Assuntos
Rutênio/química , Morte Celular , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Estrutura Molecular
14.
Proc Natl Acad Sci U S A ; 109(18): 7008-12, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22509033

RESUMO

Mammals are characterized by the complex adaptations of their dentition, which are an indication that diet has played a critical role in their evolutionary history. Although much attention has focused on diet and the adaptations of specific taxa, the role of diet in large-scale diversification patterns remains unresolved. Contradictory hypotheses have been proposed, making prediction of the expected relationship difficult. We show that net diversification rate (the cumulative effect of speciation and extinction), differs significantly among living mammals, depending upon trophic strategy. Herbivores diversify fastest, carnivores are intermediate, and omnivores are slowest. The tempo of transitions between the trophic strategies is also highly biased: the fastest rates occur into omnivory from herbivory and carnivory and the lowest transition rates are between herbivory and carnivory. Extant herbivore and carnivore diversity arose primarily through diversification within lineages, whereas omnivore diversity evolved by transitions into the strategy. The ability to specialize and subdivide the trophic niche allowed herbivores and carnivores to evolve greater diversity than omnivores.


Assuntos
Evolução Biológica , Dieta , Mamíferos/classificação , Mamíferos/fisiologia , Adaptação Fisiológica , Animais , Biodiversidade , Carnivoridade , Bases de Dados Factuais , Ecossistema , Extinção Biológica , Herbivoria , Humanos , Filogenia
15.
J Nucl Med ; 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39266290

RESUMO

Mutations of p53 protein occur in over half of all cancers, with profound effects on tumor biology. We present the first-to our knowledge-method for noninvasive visualization of p53 in tumor tissue in vivo, using SPECT, in 3 different models of cancer. Methods: Anti-p53 monoclonal antibodies were conjugated to the cell-penetrating transactivator of transcription (TAT) peptide and a metal ion chelator and then radiolabeled with 111In to allow SPECT imaging. 111In-anti-p53-TAT conjugates were retained longer in cells overexpressing p53-specific than non-p53-specific 111In-mIgG (mouse IgG from murine plasma)-TAT controls, but not in null p53 cells. Results: In vivo SPECT imaging showed enhanced uptake of 111In-anti-p53-TAT, versus 111In-mIgG-TAT, in high-expression p53R175H and medium-expression wild-type p53 but not in null p53 tumor xenografts. The results were confirmed in mice bearing genetically engineered KPC mouse-derived pancreatic ductal adenocarcinoma tumors. Imaging with 111In-anti-p53-TAT was possible in KPC mice bearing spontaneous p53R172H pancreatic ductal adenocarcinoma tumors. Conclusion: We demonstrate the feasibility of noninvasive in vivo molecular imaging of p53 in tumor tissue using a radiolabeled TAT-modified monoclonal antibody.

16.
Adv Simul (Lond) ; 8(1): 26, 2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-37950313

RESUMO

The Implicit Theory of Mindset proposes two different mindsets that sit at opposite ends of a spectrum: a fixed mindset versus a growth mindset. With a fixed mindset, an individual believes they are born with a certain amount of an attribute, and so their potential is both pre-determined and static. With a growth mindset, an individual believes their attributes are malleable and can strengthen over time with repeated effort, adaptable learning strategies, and challenge seeking. Adoption of a growth mindset is associated with improved academic success, more effective learning strategies, increased resilience in the face of adversity, and better mental wellbeing.The theoretical underpinning of psychological safety resonates with the Implicit Theory of Mindset as it infers that a significant number of simulation participants have a fixed mindset and are therefore more likely to be fearful of making an error. The simulation community agree that participants need to feel comfortable making errors for simulation to be successful. The key word here is comfortable. Participants feeling comfortable to make errors just scratches the surface of adopting a growth mindset. With a growth mindset, participants see errors as a positive in the simulation experience, an inevitability of the learning process, evidence that they are adequately challenging themselves to improve.Encouraging adoption of a growth mindset in participants is a powerful addition to the establishment of psychological safety because a growth mindset will re-frame participants' experiences of social comparison from negative to positive and optimize information processing. We propose a novel idea: simulation educators should be explicit in the pre-brief about what a growth mindset is and its associated benefits to encourage its adoption during the simulation activity-a simulation growth mindset intervention. If this is not possible due to time constraints, an online module or article about growth mindset would be appropriate as pre-reading to encourage adoption of a growth mindset in participants. The message is not that a simulation growth mindset intervention should replace the focus on psychological safety but rather that it should be used synergistically to provide the highest quality simulation experience.

17.
EJNMMI Res ; 12(1): 67, 2022 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-36210377

RESUMO

PURPOSE: Radiopharmaceuticals targeting poly(ADP-ribose) polymerase (PARP) have emerged as promising agents for cancer diagnosis and therapy. PARP enzymes are expressed in both cancerous and normal tissue. Hence, the injected mass, molar activity and potential pharmacological effects are important considerations for the use of radiolabelled PARP inhibitors for diagnostic and radionuclide therapeutic applications. Here, we performed a systematic evaluation by varying the molar activity of [18F]olaparib and the injected mass of [TotalF]olaparib to investigate the effects on tumour and normal tissue uptake in two subcutaneous human glioblastoma xenograft models. METHODS: [18F]Olaparib uptake was evaluated in the human glioblastoma models: in vitro on U251MG and U87MG cell lines, and in vivo on tumour xenograft-bearing mice, after administration of [TotalF]olaparib (varying injected mass: 0.04-8.0 µg, and molar activity: 1-320 GBq/µmol). RESULTS: Selective uptake of [18F]olaparib was demonstrated in both models. Tumour uptake was found to be dependent on the injected mass of [TotalF]olaparib (µg) but not the molar activity. An injected mass of 1 µg resulted in the highest tumour uptake (up to 6.9 ± 1.3%ID/g), independent of the molar activity. In comparison, both the lower and higher injected masses of [TotalF]olaparib resulted in lower relative tumour uptake (%ID/g; P < 0.05). Ex vivo analysis of U87MG xenograft sections showed that the heterogeneity in [18F]olaparib intratumoural uptake correlated with PARP1 expression. Substantial upregulation of PARP1-3 expression was observed after administration of [TotalF]olaparib (> 0.5 µg). CONCLUSION: Our findings show that the injected mass of [TotalF]olaparib has significant effects on tumour uptake. Moderate injected masses of PARP inhibitor-derived radiopharmaceuticals may lead to improved relative tumour uptake and tumour-to-background ratio for cancer diagnosis and radionuclide therapy.

18.
Br J Gen Pract ; 72(721): e571-e580, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35760566

RESUMO

BACKGROUND: Advance (anticipatory) care planning (ACP) requires discussions between patients and healthcare professionals about planning for future deterioration in health. ACP improves care coordination but uptake is limited and often deferred. AIM: To assess the feasibility and acceptability to patients, carers, and GPs of a primary care ACP intervention for people with incurable oesophageal, gastric, or pancreatic cancer. DESIGN AND SETTING: A 12-month feasibility randomised controlled trial (RCT) in a Scottish Cancer Network. METHOD: Patients aged ≥18 years starting palliative oncology treatment were randomised 1:1 to an ACP intervention or standard care. Patients in the intervention group received an oncologist letter supporting them to request a GP review along with a patient information leaflet about ACP. Pre-specified analyses with masking included trial recruitment and retention, ACP completion, and quality-of-life questionnaires (EuroQol EQ-5D-5L and ICECAP Supportive Care Measure) at baseline, 6, 12, 24, and 48 weeks. Qualitative interviews with purposive sampling explored patient, carer, and GP experiences. RESULTS: Of 99 eligible participants (269 screened), 46% were recruited (n = 46) and randomised; 25 to intervention and 21 to control. By 12 weeks, 45% (n = 9/20) of the individuals in the intervention and 59% (n = 10/17) in the control group had a documented ACP plan. By 24 weeks, 30% (n = 14) had died; in the remaining participants quality of life was maintained at 24 weeks except for physical symptoms. Social norms associating ACP with dying were prevalent among 23 participants interviewed. No psychological or clinical harms were identified. CONCLUSION: An RCT of ACP for people with incurable cancer in primary care is feasible. Patient, carer, and GP attitudes and behaviours determined acceptability and timing of care planning.


Assuntos
Planejamento Antecipado de Cuidados , Neoplasias Gastrointestinais , Adolescente , Adulto , Estudos de Viabilidade , Neoplasias Gastrointestinais/terapia , Humanos , Cuidados Paliativos , Atenção Primária à Saúde
19.
iScience ; 25(10): 105101, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36212022

RESUMO

Understanding variation of traits within and among species through time and across space is central to many questions in biology. Many resources assemble species-level trait data, but the data and metadata underlying those trait measurements are often not reported. Here, we introduce FuTRES (Functional Trait Resource for Environmental Studies; pronounced few-tress), an online datastore and community resource for individual-level trait reporting that utilizes a semantic framework. FuTRES already stores millions of trait measurements for paleobiological, zooarchaeological, and modern specimens, with a current focus on mammals. We compare dynamically derived extant mammal species' body size measurements in FuTRES with summary values from other compilations, highlighting potential issues with simply reporting a single mean estimate. We then show that individual-level data improve estimates of body mass-including uncertainty-for zooarchaeological specimens. FuTRES facilitates trait data integration and discoverability, accelerating new research agendas, especially scaling from intra- to interspecific trait variability.

20.
BMJ Case Rep ; 14(9)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580126

RESUMO

The advent of immunotherapy has revolutionised the treatment of metastatic lung cancer and it has recently been established as the standard of care in the radical treatment of lung cancer. However, immune-related adverse events (IrAEs) frequently occur in patients treated with immunotherapy, and rare IrAEs continue to be identified. We report a case of immunotherapy-induced coeliac disease due to adjuvant durvalumab post-chemoradiotherapy in a patient receiving curative treatment for lung cancer. The patient had raised anti-tissue transglutaminase IgA and histological findings consistent with coeliac disease. This is the first published case report of probable immunotherapy-induced coeliac disease both with the immunotherapy drug durvalumab and in the curative lung cancer setting.


Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Doença Celíaca , Neoplasias Pulmonares , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Doença Celíaca/complicações , Doença Celíaca/terapia , Humanos , Imunoterapia/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico
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