From corners to community: exploring medical students' sense of belonging through co-creation in clinical learning.

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.

Impact of changing climate on bryophyte contributions to terrestrial water, carbon, and nitrogen cycles.

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.

From safety net to trampoline: elevating learning with growth mindset in healthcare simulation.

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.

What is a mammalian omnivore? Insights into terrestrial mammalian diet diversity, body mass and evolution.

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.

Correlation between molar activity, injection mass and uptake of the PARP targeting radiotracer [18F]olaparib in mouse models of glioma.

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.

A solution to the challenges of interdisciplinary aggregation and use of specimen-level trait data.

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.

Advance care planning in primary care for patients with gastrointestinal cancer: feasibility randomised trial.

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.

Clinicopathological Determinants of Recurrence Risk and Survival in Mucinous Ovarian Carcinoma.

Mucinous ovarian carcinoma (MOC) is a unique form of ovarian cancer. MOC typically presents at early stage but demonstrates intrinsic chemoresistance; treatment of advanced-stage and relapsed disease is therefore challenging. We harness a large retrospective MOC cohort to identify factors associated with recurrence risk and survival. A total of 151 MOC patients were included. The 5 year disease-specific survival (DSS) was 84.5%. Risk of subsequent recurrence after a disease-free period of 2 and 5 years was low (8.3% and 5.6% over the next 10 years). The majority of cases were FIGO stage I (35.6% IA, 43.0% IC). Multivariable analysis identified stage and pathological grade as independently associated with DSS (p < 0.001 and p < 0.001). Grade 1 stage I patients represented the majority of cases (53.0%) and demonstrated exceptional survival (10 year DSS 95.3%); survival was comparable between grade I stage IA and stage IC patients, and between grade I stage IC patients who did and did not receive adjuvant chemotherapy. At 5 years following diagnosis, the proportion of grade 1, 2 and 3 patients remaining disease free was 89.5%, 74.9% and 41.7%; the corresponding proportions for FIGO stage I, II and III/IV patients were 91.1%, 76.7% and 19.8%. Median post-relapse survival was 5.0 months. Most MOC patients present with low-grade early-stage disease and are at low risk of recurrence. New treatment options are urgently needed to improve survival following relapse, which is associated with extremely poor prognosis.

Immunotherapy-induced coeliac disease in curative lung cancer.

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.

Radiolabeled cCPE Peptides for SPECT Imaging of Claudin-4 Overexpression in Pancreatic Cancer.

Overexpression of tight-junction protein claudin-4 has been detected in primary and metastatic pancreatic cancer tissue and is associated with better prognosis in patients. Noninvasive measurement of claudin-4 expression by imaging methods could provide a means for accelerating detection and stratifying patients into risk groups. Clostridium perfringens enterotoxin (CPE) is a natural ligand for claudin-4 and holds potential as a targeting vector for molecular imaging of claudin-4 overexpression. A glutathione S-transferases (GST)-tagged version of the C terminus of CPE (cCPE) was previously used to delineate claudin-4 overexpression by SPECT but showed modest binding affinity and slow blood clearance in vivo. Methods: On the basis of the crystal structure of cCPE, a series of smaller cCPE194-319 mutants with putatively improved binding affinity for claudin-4 was generated by site-directed mutagenesis. All peptides were conjugated site-specifically on a C-terminal cysteine using maleimide-diethylenetriamine pentaacetate to enable radiolabeling with 111In. The binding affinity of all radioconjugates was evaluated in claudin-4-expressing PSN-1 cells and HT1080-negative controls. The specificity of all cCPE mutants to claudin-4 was assessed in HT1080 cells stably transfected with claudin-4. SPECT/CT imaging of BALB/c nude mice bearing PSN-1 or HT1080 tumor xenografts was performed to determine the claudin-4-targeting ability of these peptides in vivo. Results: Uptake of all cCPE-based radioconjugates was significantly higher in PSN-1 cells than in HT1080-negative controls. All peptides showed a marked improvement in affinity for claudin-4 in vitro when compared with previously reported values (dissociation constant: 2.2 ± 0.8, 3 ± 0.1, 4.2 ± 0.5, 10 ± 0.9, and 9.7 ± 0.7 nM). Blood clearance of [111In]In-cCPE194-319, as measured by SPECT, was considerably faster than that of [111In]In-cCPE.GST (half-life, <1 min). All radiopeptides showed significantly higher accumulation in PSN-1 xenografts than in HT1080 tumors at 90 min after injection of the tracer ([111In]In-cCPE194-319, 2.7 ± 0.8 vs. 0.4 ± 0.1 percentage injected dose per gram [%ID/g], P < 0.001; [111In]In-S313A, 2.3 ± 0.9 vs. 0.5 ± 0.1 %ID/g, P < 0.01; [111In]In-S307A + N309A + S313A, 2 ± 0.4 vs. 0.3 ± 0.1 %ID/g, P < 0.01; [111In]In-D284A, 2 ± 0.2 vs. 0.7 ± 0.1 %ID/g, P < 0.05; [111In]In-L254F + K257D, 6.3 ± 0.9 vs. 0.7 ± 0.2 %ID/g, P < 0.001). Conclusion: These optimized cCPE-based SPECT imaging agents show great promise as claudin-4-targeting vectors for in vivo imaging of claudin-4 overexpression in pancreatic cancer.

[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging.

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1-3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP3, and to investigate its potential for PARP targeting in vivo. METHODS: Using the Cu-mediated 18F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the 18F-labelled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [18F]AZD2461 in vitro was assessed in a range of pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP expression and in vivo in xenograft-bearing mice. Blocking experiments were performed with both olaparib and AZD2461. RESULTS: [18F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9 % ± 3 % and 3 % ± 1 % activity yields non-decay corrected). [18F]AZD2461 was taken up in vivo in PARP1-expressing tumours, and the highest uptake was observed for PSN-1 cells (7.34 ± 1.16 %ID/g). In vitro blocking experiments showed a lesser ability of olaparib to reduce [18F]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461. CONCLUSION: Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents.

Induction of a Four-Way Junction Structure in the DNA Palindromic Hexanucleotide 5'-d(CGTACG)-3' by a Mononuclear Platinum Complex.

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.

Tumor Imaging Using Radiolabeled Matrix Metalloproteinase-Activated Anthrax Proteins.

Increased activity of matrix metalloproteinases (MMPs) is associated with worse prognosis in different cancer types. The wild-type protective antigen (PA-WT) of the binary anthrax lethal toxin was modified to form a pore in cell membranes only when cleaved by MMPs (to form PA-L1). Anthrax lethal factor (LF) is then able to translocate through these pores. Here, we used a 111In-radiolabeled form of LF with the PA/LF system for noninvasive in vivo imaging of MMP activity in tumor tissue by SPECT. Methods: MMP-mediated activation of PA-L1 was correlated to anthrax receptor expression and MMP activity in a panel of cancer cells (HT1080, MDA-MB-231, B8484, and MCF7). Uptake of 111In-radiolabeled PA-L1, 111In-PA-WTK563C, or 111In-LFE687A (a catalytically inactive LF mutant) in tumor and normal tissues was measured using SPECT/CT imaging in vivo. Results: Activation of PA-L1 in vitro correlated with anthrax receptor expression and MMP activity (HT1080 > MDA-MB-231 > B8484 > MCF7). PA-L1-mediated delivery of 111In-LFE687A was demonstrated and was corroborated using confocal microscopy with fluorescently labeled LFE687A Uptake was blocked by the broad-spectrum MMP inhibitor GM6001. In vivo imaging showed selective accumulation of 111In-PA-L1 in MDA-MB-231 tumor xenografts (5.7 ± 0.9 percentage injected dose [%ID]/g) at 3 h after intravenous administration. 111In-LFE687A was selectively delivered to MMP-positive MDA-MB-231 tumor tissue by MMP-activatable PA-L1 (5.98 ± 0.62 %ID/g) but not by furin-cleavable PA-WT (1.05 ± 0.21 %ID/g) or a noncleavable PA variant control, PA-U7 (2.74 ± 0.24 %ID/g). Conclusion: Taken together, our results indicate that radiolabeled forms of mutated anthrax lethal toxin hold promise for noninvasive imaging of MMP activity in tumor tissue.

PET Imaging of PARP Expression Using 18F-Olaparib.

Poly(ADP-ribose) polymerase (PARP) inhibitors are increasingly being studied as cancer drugs, as single agents, or as a part of combination therapies. Imaging of PARP using a radiolabeled inhibitor has been proposed for patient selection, outcome prediction, dose optimization, genotoxic therapy evaluation, and target engagement imaging of novel PARP-targeting agents. Methods: Here, via the copper-mediated 18F-radiofluorination of aryl boronic esters, we accessed, for the first time (to our knowledge), the 18F-radiolabeled isotopolog of the Food and Drug Administration-approved PARP inhibitor olaparib. The use of the 18F-labeled equivalent of olaparib allows direct prediction of the distribution of olaparib, given its exact structural likeness to the native, nonradiolabeled drug. Results:18F-olaparib was taken up selectively in vitro in PARP-1-expressing cells. Irradiation increased PARP-1 expression and 18F-olaparib uptake in a radiation-dose-dependent fashion. PET imaging in mice showed specific uptake of 18F-olaparib in tumors expressing PARP-1 (3.2% ± 0.36% of the injected dose per gram of tissue in PSN-1 xenografts), correlating linearly with PARP-1 expression. Two hours after irradiation of the tumor (10 Gy), uptake of 18F-olaparib increased by 70% (P = 0.025). Conclusion: Taken together, we show that 18F-olaparib has great potential for noninvasive tumor imaging and monitoring of radiation damage.

Selective Preparation of a Heteroleptic Cyclometallated Ruthenium Complex Capable of Undergoing Photosubstitution of a Bidentate Ligand.

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.

Photochemical Resolution of a Thermally Inert Cyclometalated Ru(phbpy)(N-N)(Sulfoxide)+ Complex.

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.

A Red-Light-Activated Ruthenium-Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells.

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.

Frontier orbitals of photosubstitutionally active ruthenium complexes: an experimental study of the spectator ligands' electronic properties influence on photoreactivity.

The synthesis and characterization of [Ru(tpy)(R2bpy)(L)](X)n complexes (tpy = 2,2':6',2''-terpyridine, R2bpy = 4,4'-dimethyl-2,2'-bipyridine (dmbpy), or 4,4'-bis(trifluoromethyl)-2,2'-bipyridine (tfmbpy), X = Cl- or PF6-, and n = 1 or 2) are described. The dmbpy and tfmbpy bidentate ligands allow for investigating the effects of electron-donating and electron-withdrawing ligands, respectively, on the frontier orbital energetics as well as the photoreactivity of these ruthenium polypyridyl complexes for five prototypical monodentate ligands L = Cl-, H2O, CH3CN, 2-(methylthio)ethanol (Hmte), or pyridine. According to spectroscopic and electrochemical studies, the dmbpy analogues displayed a singlet metal-to-ligand charge transfer (1MLCT) transition at higher energy than the tfmbpy analogues. The shift of the 1MLCT to higher energy results from the lowest unoccupied molecular orbital (LUMO) for the dmbpy analogues being tpy-based, whereas for the tfmbpy analogues orbital inversion occurs resulting in a tfmbpy-based LUMO. The energy level of the highest occupied molecular orbital (HOMO) was considerably affected by the nature of the monodentate ligand. Visible light irradiation of the complexes demonstrated that the tfmbpy analogue increased the rate and quantum yields of photosubstitution reactions, compared to the dmbpy analogue, suggesting that the electron-withdrawing substituents allowed better thermal accessibility of the triplet metal-centered (3MC) state from the photochemically generated triplet metal-to-ligand charge transfer (3MLCT) excited state. A correlation between the photolability of the monodentate ligands and the electrochemical reversibility of the metal-based oxidation is also reported.