Illuminating the Numbers: Integrating Mathematical Models to Optimize Photomedicine Dosimetry and Combination Therapies

Cancer photomedicine offers unique mechanisms for inducing local tumor damage with the potential to stimulate local and systemic anti-tumor immunity. Optically-active nanomedicine offers these features as well as spatiotemporal control of tumor-focused drug release to realize synergistic combination therapies. Achieving quantitative dosimetry is a major challenge, and dosimetry is fundamental to photomedicine for personalizing and tailoring therapeutic regimens to specific patients and anatomical locations. The challenge of dosimetry is perhaps greater for photomedicine than many standard therapies given the complexity of light delivery and light–tissue interactions as well as the resulting photochemistry responsible for tumor damage and drug-release, in addition to the usual intricacies of therapeutic agent delivery. An emerging multidisciplinary approach in oncology utilizes mathematical and computational models to iteratively and quantitively analyze complex dosimetry, and biological response parameters. These models are parameterized by preclinical and clinical observations and then tested against previously unseen data. Such calibrated and validated models can be deployed to simulate treatment doses, protocols, and combinations that have not yet been experimentally or clinically evaluated and can provide testable optimal treatment outcomes in a practical workflow. Here, we foresee the utility of these computational approaches to guide adaptive therapy, and how mathematical models might be further developed and integrated as a novel methodology to guide precision photomedicine

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Two-photon peak molecular brightness spectra evince long-wavelength advantages for hyperspectral multiplexing in a tissue phantom

We present two-photon peak molecular brightness spectra for eight fluorophores between 700 and 1300 nm. Longer wavelength excitation is shown to offer advantages for simultaneous six dye excitation and hyperspectral multiplexing in a tissue phantom.</jats:p

Two-photon peak molecular brightness spectra reveal long-wavelength enhancements of multiplexed imaging depth and photostability

The broad use of two-photon microscopy has been enabled in part by Ti:Sapphire femtosecond lasers, which offer a wavelength-tunable source of pulsed excitation. Action spectra have thus been primarily reported for the tunable range of Ti:Sapphire lasers (∼700–1000 nm). However, longer wavelengths offer deeper imaging in tissue via reduced scattering and spectral dips in water absorption, and new generations of pulsed lasers offer wider tunable ranges. We present the peak molecular brightness spectra for eight Alexa Fluor dyes between 700–1300 nm as a first-order surrogate for action spectra measured with an unmodified commercial microscope, which reveal overlapping long-wavelength excitation peaks with potential for multiplexed excitation. We demonstrate simultaneous single-wavelength excitation of six spectrally overlapping fluorophores using either short (∼790 nm) or long (∼1090 nm) wavelengths, and that the newly characterized excitation peaks measured past 1000 nm offer improved photostability and enhanced fidelity of linear spectral unmixing at depth compared to shorter wavelengths.</jats:p

Custom fabrication and mode-locked operation of a femtosecond fiber laser for multiphoton microscopy

AbstractSolid-state femtosecond lasers have stimulated the broad adoption of multiphoton microscopy in the modern laboratory. However, these devices remain costly. Fiber lasers offer promise as a means to inexpensively produce ultrashort pulses of light suitable for nonlinear microscopy in compact, robust and portable devices. Although encouraging, the initial methods reported in the biomedical engineering community to construct home-built femtosecond fiber laser systems overlooked fundamental aspects that compromised performance and misrepresented the significant financial and intellectual investments required to build these devices. Here, we present a practical protocol to fabricate an all-normal-dispersion ytterbium (Yb)-doped femtosecond fiber laser oscillator using commercially-available parts (plus standard optical components and extra-cavity accessories) as well as basic fiber splicing and laser pulse characterization equipment. We also provide a synthesis of established protocols in the laser physics community, but often overlooked in other fields, to verify true versus seemingly (partial or noise-like) mode-locked performance. The approaches described here make custom fabrication of femtosecond fiber lasers more accessible to a wide range of investigators and better represent the investments required for the proper laser design, fabrication and operation.</jats:p