Photochemical internalisation of chemotherapy potentiates killing of multidrug-resistant breast and bladder cancer cells

Multidrug resistance (MDR) is the major confounding factor in adjuvant solid tumour chemotherapy. Increasing intracellular amounts of chemotherapeutics to circumvent MDR may be achieved by a novel delivery method, photochemical internalisation (PCI). PCI consists of the co-administration of drug and photosensitiser; upon light activation the latter induces intracellular release of organelle-bound drug. We investigated whether co-administration of hypericin (photosensitiser) with mitoxantrone (MTZ, chemotherapeutic) plus illumination potentiates cytotoxicity in MDR cancer cells. We mapped the extent of intracellular co-localisation of drug/photosensitiser. We determined whether PCI altered drug-excreting efflux pump P-glycoprotein (Pgp) expression or function in MDR cells. Bladder and breast cancer cells and their Pgp-overexpressing MDR subclones (MGHU1, MGHU1/R, MCF-7, MCF-7/R) were given hypericin/MTZ combinations, with/without blue-light illumination. Pilot experiments determined appropriate sublethal doses for each. Viability was determined by the 3-[4,5-dimethylthiazolyl]-2,5-diphenyltetrazolium bromide assay. Intracellular localisation was mapped by confocal microscopy. Pgp expression was detected by immunofluorescence and Pgp function investigated by Rhodamine123 efflux on confocal microscopy. MTZ alone (0.1–0.2 μg ml−1) killed up to 89% of drug-sensitive cells; MDR cells exhibited less cytotoxicity (6–28%). Hypericin (0.1–0.2 μM) effects were similar for all cells; light illumination caused none or minimal toxicity. In combination, MTZ /hypericin plus illumination, potentiated MDR cell killing, vs hypericin or MTZ alone. (MGHU1/R: 38.65 and 36.63% increase, P<0.05; MCF-7/R: 80.2 and 46.1% increase, P<0.001). Illumination of combined MTZ/hypericin increased killing by 28.15% (P<0.05 MGHU1/R) compared to dark controls. Intracytoplasmic vesicular co-localisation of MTZ/hypericin was evident before illumination and at serial times post-illumination. MTZ was always found in sensitive cell nuclei, but not in dark resistant cell nuclei. In illuminated resistant cells there was some mobilisation of MTZ into the nucleus. Pgp expression remained unchanged, regardless of drug exposure. Pgp efflux was blocked by the Pgp inhibitor verapamil (positive control) but not impeded by hypericin. The increased killing of MDR cancer cells demonstrated is consistent with PCI. PCI is a promising technique for enhancing treatment efficacy

The prevalence and influence of circumstellar material around hydrogen-rich supernova progenitors

Narrow transient emission lines (flash-ionization features) in early supernova (SN) spectra trace the presence of circumstellar material (CSM) around the massive progenitor stars of core-collapse SNe. The lines disappear within days after the SN explosion, suggesting that this material is spatially confined, and originates from enhanced mass loss shortly (months to a few years) prior to explosion. We performed a systematic survey of H-rich (Type II) SNe discovered within less than two days from explosion during the first phase of the Zwicky Transient Facility (ZTF) survey (2018-2020), finding thirty events for which a first spectrum was obtained within $< 2$ days from explosion. The measured fraction of events showing flash ionisation features ($>36\%$ at $95\%$ confidence level) confirms that elevated mass loss in massive stars prior to SN explosion is common. We find that SNe II showing flash ionisation features are not significantly brighter, nor bluer, nor more slowly rising than those without. This implies that CSM interaction does not contribute significantly to their early continuum emission, and that the CSM is likely optically thin. We measured the persistence duration of flash ionisation emission and find that most SNe show flash features for $\approx 5$ days. Rarer events, with persistence timescales $>10$ days, are brighter and rise longer, suggesting these may be intermediate between regular SNe II and strongly-interacting SNe IIn

Annie, a Tool for Integrating Ergonomics in the Design of Car Interiors

An example of a result from a long-term cooperation with\ua0Lund University (together with professor Roland Axelsson at the Department\ua0for Work Environment) there some of the authors. (Engstr\uf6m)\ua0gained extensive\ua0grants (Wallenberg Stifelsen regarding\ua0equipment as well as other founding from e.g. the Swedish Work Environment Found)

ANNIE, a Tool for Integrating Ergonomics in the Design of Car Interiors

An example of a result from a long-term cooperation with\ua0Lund University (together with professor Roland Akselsson at the Department\ua0for Work Environment) there some of the authors (Engstr\uf6m)\ua0gained extensive\ua0grants (Wallenberg Stifelsen regarding\ua0equipment as well as other founding from e.g. the Swedish Work Environment Found). In this case the just mentioned EU-financing

The prevalence and influence of circumstellar material around hydrogen-rich supernova progenitors

Narrow transient emission lines (flash-ionization features) in early supernova (SN) spectra trace the presence of circumstellar material (CSM) around the massive progenitor stars of core-collapse SNe. The lines disappear within days after the SN explosion, suggesting that this material is spatially confined, and originates from enhanced mass loss shortly (months to a few years) prior to explosion. We performed a systematic survey of H-rich (Type II) SNe discovered within less than two days from explosion during the first phase of the Zwicky Transient Facility (ZTF) survey (2018-2020), finding thirty events for which a first spectrum was obtained within $36\%$ at $95\%$ confidence level) confirms that elevated mass loss in massive stars prior to SN explosion is common. We find that SNe II showing flash ionisation features are not significantly brighter, nor bluer, nor more slowly rising than those without. This implies that CSM interaction does not contribute significantly to their early continuum emission, and that the CSM is likely optically thin. We measured the persistence duration of flash ionisation emission and find that most SNe show flash features for $\approx 5$ days. Rarer events, with persistence timescales $>10$ days, are brighter and rise longer, suggesting these may be intermediate between regular SNe II and strongly-interacting SNe IIn