Repurposing Proton Beam Therapy through Novel Insights into Tumour Radioresistance.

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.

Addition of biphasic insulin aspart 30 to optimized metformin and pioglitazone treatment of type 2 diabetes mellitus: The ACTION Study (Achieving Control Through Insulin plus Oral ageNts).

AIM: Efficacy and safety of biphasic insulin aspart (BIAsp 30, 30% short-acting and 70% intermediate-acting insulin aspart) added to an optimized treatment of metformin and pioglitazone (met/pio) were compared with treatment with optimized met/pio in type 2 diabetes patients. METHODS: This randomized, 34-week, parallel-group study enrolled insulin-naive, type 2 diabetes patients (HbA(1c) 7.5-12.0%) previously using two oral antidiabetic (OAD) agents. During an 8-week run-in period, treatment was changed to met/pio and doses were adjusted up to 2500 mg/day and 30 or 45 mg/day respectively. Subjects either continued met/pio alone or added BIAsp 30 initiated at 6 units twice daily and titrated to target plasma glucose (PG) (4.4-6.1 mmol/l). RESULTS: At end-of-study, subjects treated with BIAsp 30+met/pio (n = 93) had a mean (+/-s.d.) HbA(1c) reduction significantly greater than treatment with met/pio (n = 88) (1.5% +/- 1.1 vs. 0.2% +/- 0.9, p < 0.0001 between groups). Subjects treated with BIAsp 30+met/pio were more likely to reach The American Association of Clinical Endocrinologists and European Association for the Study of Diabetes/American Diabetes Association HbA(1c) targets of < or =6.5 and <7.0%, respectively, than with met/pio only (HbA(1c)< or =6.5%: 59 vs. 12%; HbA(1c) <7.0%: 76 vs. 24%). At end-of-study, self-monitored glucose profile values at all eight daily time points were significantly less for the BIAsp 30+met/pio group compared with the met/pio group, and minor hypoglycaemia (defined as PG < 3.1 mmol/l) was more frequent (8.3 vs. 0.1 events/year, p < 0.001). Both groups gained weight during treatment (BIAsp 30+met/pio, 4.6 +/- 4.3 kg; met/pio, 0.8 +/- 3.2 kg; p < 0.001). CONCLUSION: Addition of insulin in type 2 patients treated with met/pio is an effective way to achieve glycaemic targets. Treatment with BIAsp 30+met/pio achieved significantly greater reduction in HbA(1c), as compared with met/pio alone. In patients with type 2 diabetes poorly controlled by 2 OADs, more achieved glycaemic targets using BIAsp 30+met/pio than using met/pio alone.

Negative association between acrylamide exposure and body composition in adults: NHANES, 2003-2004.

BACKGROUND/OBJECTIVES: Acrylamide is present in mainstream cigarette smoke and in some food prepared at high temperature. Animal studies have shown that acrylamide exposure reduces body weight. Prenatal exposure to acrylamide also has been linked to reduced birth weight in human. Whether acrylamide exposure is associated with altered body compositions in adults is not clear. SUBJECTS/METHODS: We selected 3623 subjects (aged ⩾20 years) from a National Health and Nutrition Examination Survey (NHANES) in 2003-2004 to determine the relationship among hemoglobin adducts of acrylamide (HbAA), hemoglobin adducts of glycidamide (HbGA) and body composition (body measures, bioelectrical impedance analysis (BIA), dual energy x-ray absorptiometry (DXA)). Data were adjusted for potential confounding variables. RESULTS: The geometric means and 95% CI concentrations of HbAA and HbGA were 60.48 (59.32-61.65) pmol/g Hb and 55.64 (54.40-56.92) pmol/g Hb, respectively. After weighting for sampling strategy, we identified that one-unit increase in natural log-HbAA, but not HbGA, was associated with reduction in body measures (body weight, body mass index (BMI), subscapular/triceps skinfold), parameters of BIA (fat-free mass, fat mass, percent body fat, total body water) and parameters of DXA (android fat mass, android percent fat, gynoid fat/lean mass, gynoid percent mass, android to gynoid ratio). Subgroup analysis showed that these associations were more evident in subjects at younger age, male gender, whites, lower education level, active smokers and those with lower BMI. CONCLUSIONS: Higher concentrations of HbAA are associated with a decrease in body composition in the US general population. Further studies are warranted to clarify this association.

Assessment of proteinuria by using the protein/creatinine ratio of single-voided urine.

Quantitative 24-hour urine protein excretion is used in the diagnosis, the monitoring of therapeutic effects and the prognosis of renal disease. However, this method is time-consuming, cumbersome and often inaccurate. Many studies have shown that the single voided urine protein/creatinine (Pr/Cr) ratio relates well with 24-hour urine protein excretion and can be substituted for evaluating some conditions. In our study, 41 patient with renal disease (25 men, 16 women) with a mean age of 43 years (range, 20-79 years), not only collected 24-hour urine, but also collected single voided urine at four different times. There was an excellent correlation between 24-hour urine protein excretion and the single voided urine Pr/Cr ratio at various degrees of creatinine clearance and ranges of proteinuria. The highest correlation was found in urine specimens collected at 16:00 hours with a correlation coefficient (r) of 0.91. Other urine specimens also showed a good relation with a correlation coefficient of above 0.80. The creatinine clearance (Ccr) greater than or equal to 70 ml/min group showed a better relationship than the Ccr less than 70 ml/min group. The proteinuria more than 1.0 g/day group also showed a better relationship than the group with proteinuria of less than 1.0 g/day. However, these differences were not statistically significant. No significant differences between the different age groups or sexes, using the single voided urine Pr/Cr ratio to estimate the 24-hour urine protein excretion were found. It is concluded that the single voided urine Pr/Cr ratio correlates highly with 24-hour urine protein excretion and could be an alternative means for disease monitoring and screening.

Soliton interaction in the presence of loss and periodic amplification in optical fibers.

The stability of soliton transmission in the presence of loss and periodic amplification is studied when the pulses are closely separated. It is shown that stable transmission can be achieved when solitons are launched with unequal amplitudes to avoid mutual interaction.

Suppression of self-pulsing in an erbium-doped fiber laser.

We propose a scheme whereby the self-pulsation that commonly occurs in an erbium-doped fiber laser can be suppressed. The scheme consists of the addition of a low-power laser as an auxiliary pump. The required auxiliary pump power is only a few percent of the output lasing power. There is reasonable agreement between experimental and theoretical results.

Optical switching in twin-core erbium-doped fibers.

We report the theoretical and experimental investigation of switching in a nonlinear twin-core erbium-doped fiber coupler. It is shown that switching action takes place at a power of a fraction of 1 mW. Thus it provides a practical means of fabricating an all-optical fiber switch.

Holographic measurement of refractive-index profile in the transition region of an optical fiber preform.

The refractive-index profile at the preform-fiber transition region was measured using holographic shearing interferometry. It involved the measurements of both the horizontal and vertical deflection functions. Analysis is also given on the ray trajectories in the transition region. It is shown that the vertical deflection of the rays has a significant influence on the measurement of the horizontal deflection function which is needed for reconstruction of the index profile. It is found from measurement results that there is a variation of the index profile as the preform is transformed into fiber. This is especially pronounced at the cladding region where boron is doped.

Measurement of stresses in optical fiber and preform.

A method of measuring the stresses, residual or applied, in an optical fiber or preform is presented. It is shown that the stress profiles can be obtained from the Abel transform of the derivative of the retardation. The axial stress profile is shown to bear the same shape as the refractive-index profile. Measurement results indicate that the applied tension during the fiber drawing process is frozen into the fiber, consequently affecting the intrinsic strength of the fiber. The method of estimating the fiber drawing tension from the fiber stress profile is also given.

Nondestructive determination of refractive index profile of an optical fiber: backward light scattering method.

A new nondestructive technique is presented for determining the refractive index profile of an optical fiber from its backscattered pattern arising from a normally incident laser beam to the fiber axis. The proposed method requires no sample preparation or index matching liquid. The principle of the method is to construct a deflection function from the measured pattern. The index profile can then be determined by the inversion of an Abel integral equation. Good agreement is obtained between the index profile determined by this technique and that measured by the near-field scanning technique.

Nondestructive determination of refractive index profile of an optical fiber: fast Fourier transform method.

A nondestructive technique of determining the refractive index profile of an optical fiber is presented. This method involves collecting the pathlength data of rays passing through the fiber due to side-illumination and taking the fast Fourier transform of these data followed by a numerical integration. It is found that this technique yields results in good agreement with measurements from the near-field scanning technique. The advantage of the present method is that it can readily be extended to fibers of noncircular cross section.

Diameter determination of graded-index optical fibers from backward-scattered pattern.

The backscattered pattern of an optical fiber with arbitrary refractive-index profile is used to determine the fiber diameter. Two methods are presented: the fiber diameter can be determined either by noting the position of a particular fringe maximum or by counting the total number of fringes in the pattern. This method is fast in that it does not require any mechanical moving part, and the measurement error is 1%. This method is based on the prior knowledge of the refractive-index profile of the fiber, but it is shown that the error incurred by assuming the wrong profile is less than 1%. It is also shown in this paper that the method can be used to monitor the diameter variation while the fiber is being pulled. This is done by tracking the displacement of a particular fringe. It is shown that this method is also applicable to fibers with elliptical cross section.

Narrow-bandpass filter with gain by use of twin-core rare-earth-doped fiber.

We demonstrate both numerically and experimentally that rare-earth-doped twin-core fiber couplers can function as a narrow-bandpass wavelength filter or as a demultiplexer. The experimental bandwidth obtained is 6.5 nm. In addition, the filtered signal experiences a gain of 20 dB instead of attenuation.

Unusual case of corticobasal degeneration with tau/Gallyas-positive neuronal and glial tangles.

A 74-year-old woman with corticobasal degeneration (CBD) had a 9-year history of progressive loss of strength and rigidity of her right hand and then arm, followed by speech difficulties, dyskinesia, rigidity, spasticity and weakness of the ipsilateral lower limb, ultimately also involving the opposite side. She later developed supranuclear gaze palsy. Her memory remained intact during most of the duration of her disease. Laboratory tests and anti-Parkinsonian medications were not helpful. At autopsy, frontal lobe atrophy, discoloration of putamen (Pt) and pallor of substantia nigra (Sn) were observed. Neuronal loss and gliosis were extensive in motor cortex and milder in frontal cortex, abruptly ending at the central sulcus and junction of cingulate gyrus. "Achromatic" neurons were present. Neuronal loss and gliosis were seen in Pt and Sn and corticobasal inclusions in Sn. Numerous Gallyas/tau-positive, Bielschowsky/ubiquitin-negative coil, sickle, or coma-shaped tangles and thread-like processes were found in affected cortex, Pt and Sn. Some of the tangles were in neurons, but most occurred in astroglia, and their processes. The presence of Gallyas/tau-positive glia in CBD may have the same diagnostic significance as in progressive supranuclear palsy, analogous to the argyrophilic ubiquinated inclusions in oligodendroglia in multisystem atrophy. We suggest that in CBD: (1) cytoskeletal protein metabolism in neurons and glia can simultaneously be perturbed in certain neurodegenerative diseases, and (2) the astrocytosis in CBD may not be simply a reactive process but an integral part of the disease.

Breathing spatial solitons in non-Kerr media.

The concept of soliton internal mode is introduced to explain quantitatively the long-lived oscillations of self-guided beams, or breathing spatial solitons. Cubic-quintic nonlinearity is considered in detail, and it is shown that the existence of the internal mode affects strongly the beam propagation in non-Kerr media, leading to oscillatory dependence of the output width of the beam versus its input power.

Accurate elasto-optic probe method for measurement of coupling length in twin-core optical fiber.

The theoretical principle and experimental procedure of a new method of measuring the coupling length of a twin-core fiber are presented. This method is simple, nondestructive, and gives direct results without extensive data processing. It is based on the elasto-optic technique and had a very good spatial resolution so that coupling lengths of the order of a few millimeters can be measured. We show how this method can be applied to the measurement of the polarization coupling of birefringent noncircular twin-core fibers.

Nondestructive measurement of refractive-index profile and cross-sectional geometry of optical fiber preforms.

A modified focusing method for measuring simultaneously the refractive-index profile and the cross-sectional geometry of an optical fiber preform is presented. In this method the preform is immersed in indexmatching liquid, and collimated light is made to impinge on the preform laterally. The intensity distributions of the transmitted light are detected on two planes inside the preform core. From the recorded light intensity distributions, the deflection function is calculated. After the preform has been rotated through 180 degrees and the necessary data have been collected, a numerical inversion is performed to obtain the 2-D index profile. In this paper, the principle, the experimental setup, and results are described. The sensitivity of the method to measurement errors and the accuracy of the inversion formula were investigated by computer simulations. It was found that the error of the index profile measurement was <1%.

Couplings in spun twin-core optical fibers.

A new effect of spun twin-core fiber is observed in which the coupling between the two cores is increased with the spin rate. In addition, the cladding-mode attenuation is also increased. These effects can find many useful applications in fiber devices for optical communication, sensing, or signal processing.