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Despite improvements in radiotherapy, radioresistance remains an important clinical challenge. Radioresistance can be mediated through enhanced DNA damage response mechanisms within the tumour or through selective pressures exerted by the tumour microenvironment (TME). The effects of the TME have in recent times gained increased attention, in part due to the success of immune modulating strategies, but also through improved understanding of the downstream effects of hypoxia and dysregulated wound healing processes on mediating radioresistance. Although we have a better appreciation of these molecular mechanisms, efforts to address them through novel combination approaches have been scarce, owing to limitations of photon therapy and concerns over toxicity. At the same time, proton beam therapy (PBT) represents an advancement in radiotherapy technologies. However, early clinical results have been mixed and the clinical strategies around optimal use and patient selection for PBT remain unclear. Here we highlight the role that PBT can play in addressing radioresistance, through better patient selection, and by providing an improved toxicity profile for integration with novel agents. We will also describe the developments around FLASH PBT. Through close examination of its normal tissue-sparing effects, we will highlight how FLASH PBT can facilitate combination strategies to tackle radioresistance by further improving toxicity profiles and by directly mediating the mechanisms of radioresistance.

Purpose Improved antitumor responses have been observed in patients after combination radiation therapy (RT) and immune checkpoint blockade (ICB). Whether these clinical responses are linked to the host systemic immune system has not been elucidated. Methods and Materials In this single-institution prospective observational study, peripheral blood was longitudinally collected from 10 patients with metastatic disease who had responded to anti-PD-1/anti-PD-L1 ICB and received RT (8-50 Gy in 1-5 fractions) upon disease progression at the following timepoints: baseline (pre-RT), 1 to 2 weeks post-RT, and post-ICB (cycle 1) on reintroduction post-RT. To thoroughly characterize the interaction between combined RT-ICB and the host immune system, we performed high-dimensional, mass cytometry–based immunophenotyping of circulating lymphocytes using a 40-marker panel addressing lineage, differentiation, activation, trafficking, cytotoxicity, and costimulatory and inhibitory functions. Phenotypic expression of circulating lymphocytes was compared across patients and time points and correlated with post-RT tumor responses. Results Foremost, we demonstrated excellent posttreatment clinical responses, including 4 local responses with >50% reduction in radiated tumor size, 1 out-of-field response, and 4 patients who resumed ICB for >1 year. Baseline and post-RT immune states were highly heterogeneous among patients. Despite this interindividual heterogeneity in baseline immune states, we observed a systemic immune reaction to RT-ICB common across patients, histology, and radiation sites; a subset of pre-existing Ki-67+ CD8+ T cells were increased post-RT and further expanded upon reintroduction of ICB post-RT (2.3-fold increase, P = .02). Importantly, RT did not alter the phenotypic profile of these Ki-67+ CD8+ T cells, which was characterized by a distinct activated and differentiated effector phenotype. Conclusions Collectively, these findings point toward a sustained reinvigoration of host antitumor immunity after RT-ICB and suggest an expansion in activated Ki-67+ CD8+ T cells as a possible demonstration of this synergy, thereby providing new insights that may support the development of optimal sequencing strategies.

Background Epidermal growth factor receptor (EGFR) overexpression is characteristic in head and neck cancers and is associated with tumour regrowth following photodynamic therapy (PDT). Purpose We investigated vandetanib, which selectively blocks EGFR and vascular endothelial growth factor receptor-2 (VEGFR-2), to enhance the efficacy of PDT. Methods We assessed the in vitro therapeutic efficacy of: 1) vandetanib; 2) PDT with the photosensitizer Chlorin e6 (Fotolon®); and 3) combined PDT + vadetanib treatment in CAL-27 oral squamous cell carcinoma (OSCC) cell line by cell viability, γH2AX foci immunostaining, cell cycle arrest and western blot. We also performed in vivo tumour regression study and immunohistochemical staining of formalin-fixed paraffin-embedded (FFPE) regressed and regrown tumour tissues. Results First, we observed significantly higher cytotoxicity and residual DNA damage in vandetanib + PDT-treated CAL-27 OSCC cells than tumour cells treated with PDT alone. This is due to impaired DNA DSB repair caused by downregulation of EGFR-mediated DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activation. Next, combined vandetanib and PDT resulted in significant tumour growth delay in vivo that is linked to reduction of PDT-induced EGFR phosphorylation and cellular proliferation, along with loss of tumour vasculature. In particular, we observed significant revascularisation of the microenvironment that is associated with upregulated ERK1/2 phosphorylation in regrown tumours post-vandetanib + PDT, thereby corroborating the importance of microenvironmental modification for the observed drug-PDT synergistic interaction. Conclusion Taken together, our data suggests that vandetanib enhances the efficacy of PDT through both direct and indirect effects on the cellular DNA repair machinery and tumour microenvironment, respectively.

The effect of phytochemical tannic acid on Methicillin Resistant Staphylococcus aureus (MRSA) three clinical strains was studied individually and in combination with western antibiotic fusidic acid. The two drugs were synergistic to each other and the combined effect of the two drugs could delay or prevent the occurrence of adaptive mutations in MRSA. The possible mechanism might be the phytochemical tannic acid could potentiate the effect of fusidic acid and/or acts alternative target that results in lysis of bacteria. In this study, it was found that the mutants result from the continuous exposure of sub-minimal inhibitory concentration (MIC) of fusidic acid revealed over active efflux pump as measured by ethidium bromide (EtBr) accumulation assay. However, the parent strains have no efflux pump activity. Therefore, it can be concluded that the strains which normally don’t have efflux activity can result in over activity of efflux pump if they are being exposed by sub-MIC concentrations of western antibiotic (fusidic acid). Efflux modulating activity of tannic acid was tested against the strains with over active efflux pump activity. It was noticed that EtBr accumulation was increased with over time when the adapted strains were being exposed by sub-MIC concentrations (0.3 and 0.6 MIC) of tannic acid, meaning that phytochemical tannic acid has efflux modulating activity against MRSA strains that results in decreased in MIC of partner drug and thus, preventing its adaptive mutation.

We study the dynamics of two-component solitons in a dispersion-managed (DM) system, built as a periodic concatenation of segments of optical fibers with anomalous and normal group-velocity dispersion (GVD). The model includes, in addition to the usual GVD and nonlinear terms, birefringence and polarization-mode-dispersion (PMD), in the form of the polarization scrambling (random rotation of the polarization) taking place at randomly distributed defects. We propose a numerical algorithm for finding optimized DM solitons in such a system, which secure stable transmission over a large distance. The analysis includes effects of the PMD-induced noise, together with the noise due to the spontaneous amplifier emission, and the input-source noise. It is concluded that, if the group-velocity birefringence is not excessively large, the use of the optimized solitons makes it possible to tolerate the PMD effects in the long-haul DM link.

A gigabit soliton pulse train is shown to be generated by the use of a combination of a Figure-8 fiber laser and a Moire fiber grating. The bit rate achieved is 45.5 Gb/s and this is determined by the Bragg wavelength shift in the Moire Grating and the grating linewidth. A simple theory is presented to explain the behaviour of the pulse train as a function of the grating and fibre laser parameters. In addition to the high bit rate achieved, the setup retains the desirable features of a Figure-8 soliton fibre laser, i.e., it is strongly stable and the soliton pulse has high energy. Another desirable characteristics is that it needs a relatively low pump power of 150 mW.

The pulse–pulse interaction in a dispersion-managed fiber system is studied for the case when a nonlinear gain and spectral filtering are included into the dispersion-gain map. In this system, the pulse of any shape converges quickly to a dispersion-managed soliton. Using the technique of interaction plane, we have found stable bound states of two pulses. The effects we have studied may significantly reduce the chances of pulse coalescence in specially designed optical transmission lines.

An improvement has been made to Rouard's method for the analysis of fiber and waveguide gratings. The real reflectivity of each interface is used instead of an approximate value obtained by coupled-mode theory. The improved Rouard's method becomes a complete Rouard's method and an exact method. It is simple and independent on coupled-mode theory for no calculation of coupling coefficient required. Numerical examples of uniform and nonuniform gratings have been given.

In this paper, we show experimentally that large photosensitivity in dye-doped polymer optical fibers can be obtained with small pump power (about 1 mW) at visible wavelength. The fiber has two identical cores each doped with fluorescein, and the pump beam is launched axially into one of the cores. However, when the pump beam at UV wavelength is launched into the fiber transversely, large photosensitivity is also observed. We also show that gratings can be written in polymer fiber and preform.

We numerically analyse the effect of coupling strength random fluctuations on both dynamic and static soliton switching in symmetric nonlinear couplers. As in the cw case, the effect is generally found to be strong only near the switching regions. In the dynamical switching regime, the effect appears to increase with the length of the coupler at a rate twice as large for odd multiples of the linear coupling length, π /2, than for even ones. In the static case, the region of bistability shows the greatest change in the effect of random fluctuations, with a maximum at exactly the first bifurcation point. The solitons also appear to be quite stable against the random fluctuations in the sense that no pulse distortion or emission of dispersive radiation was detected.

The undoing of soliton interactions by optical phase conjugation (OPC) using unequal-amplitude solitons has been numerically studied and compared with the case when phase-alternation between neighbouring solitons is applied. With sufficiently large amplitude differences and appropriate bit patterns, the undoing can be significantly improved even when OPC is applied at distances where the solitons interact seriously or at longer distances after they have separated away from coalescence. This method appears to be just as effective as the best phase-alternation scenario when a phase difference of π is introduced between neighbouring time slots.

We report an investigation of pulse propagation through a recently proposed nonlinear amplifier composed of asymmetrical twin-core fibre. While the pulse is amplified and the associated noise is suppressed, we find that the pulse is strongly chirped. While the chirp in the centre of the pulse can be easily eliminated by inserting a short piece of dispersive fibre right after the amplifier, the chirp in the wings may remain and lead to the eventual destruction of the pulse. This residual chirp can be removed through a damped and radiative oscillation by judicious adjustment of the parameters of the amplifier and the dispersive fibre. Finally, we consider the effect of noise in the pulse. We discovered a threshold of the noise amplitude below which the noise is suppressed (which must be a characteristic asset of the nonlinear amplifier). Above the threshold, the noise tends to shift the centre of the pulse.

We propose a simple scheme of dark soliton generation in a fused coupler due to interaction of a bright soliton in one arm of the coupler with a long pulse of the other arm. We demonstrate also an analytical method for calculating the parameters of the generated dark soliton.

We show that the cross-phase modulation effect in a Sagnac fibre loop can be used to measure the nonlinear refractive index (n2) of the fibre. The setup is simpler than the counterparts that use the self-phase modulation effect but it gives greater sensitivity. The polarisation effect of the Sagnac loop can also be controlled and the reciprocal nature of the loop is ensured. This removes automatically the uncertainties from the thermal and some other sources.

We consider compression of higher-order solitons in asymmetric and symmetric dual-core fibers (couplers) by means of numerical simulations of the corresponding coupled nonlinear Schrodinger equations. We demonstrate that an asymmetric coupler with different dispersion coefficients in its two cores provides almost the same degree of compression for the soliton tunneling from the core with a larger dispersion into the one with a smaller dispersion as the single-core fiber with the same jump of the dispersion coefficients. The pedestal around the compressed soliton is smaller when using the coupler; however, the necessary compression length is larger for the coupler than for the single-core fiber. An advantage of using the coupler is that it allows one to avoid a junction between two pieces of the fiber with different dispersions, which is inevitable if one uses the single-core fiber. Next, we consider compression of a higher-order soliton in a symmetric coupler. We demonstrate that, using the so-called soliton effect, one can achieve a record compression ratio (approximately 20), which is larger than that for any other known soliton compressor, with a very small share of the total energy in the pedestal. The corresponding compression length is still larger than for the single-core fiber, but the compression quality is much better. Lastly, the symmetric coupler allows, in some cases, to split the incoming pulse into two nearly identical compressed pulses outcoming from the two cores.

Step-index polymer optical fibre doped with Rhodamine B at 2500 ppm level is fabricated. Using the fibre, we have achieved high-gain and high-efficiency optical amplification with a tunable wavelength range from 610 nm to 640 nm, which is significantly red-shifted toward the centre of the communication window (at 650 nm wavelength) of methyl methacrylate-based polymer optical fibre.

Coupling and switching of solitons in a nonlinear coupler whose coupling varies with longitudinal distance is examined. Within the variational approximation, an exact solution which describes complete coupling is found. The accuracy of this approximation is shown to be good.

Demonstrated are inherent problems in attempts to apply variational methods based on the lagrangian density to analysis of soliton coupling in directional couplers. A number of controversies related to this method are discussed. It is shown that only the stationary asymmetric solutions which are close to the lower bifurcation point can be described with reasonable accuracy. Comparison of the results obtained with assorted trial functions and with exact results are given. The discrepancy in describing the field evolution starting from certain initial conditions is not only quantitative but also qualitative.