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.

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.

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.

Effect of highly active antiretroviral therapy on diagnoses of sexually transmitted diseases in people with AIDS.

BACKGROUND: There has been an increase in high-risk sexual behaviour and sexually transmitted diseases (STD) during the time period when highly active antiretroviral therapy (HAART) became widely available. We examined whether taking HAART increased the risk of acquiring an STD--an epidemiological marker of unsafe sex--in people with AIDS. METHODS: We did a computerised match of people in the San Francisco STD and AIDS registries. People with AIDS who were diagnosed before 1999 and alive in November, 1995, or later, were classified as having had an STD after AIDS diagnosis or not having had an STD after AIDS diagnosis. We used a Cox proportional hazards model to see whether use of antiretroviral therapy was associated with acquiring an STD after AIDS, after adjustment for sex, age, race, HIV-1 risk category, and CD4 count at AIDS diagnosis. FINDINGS: People with AIDS who had had HAART showed an independent increase in the risk of developing an STD (hazard ratio 4.10; 95% CI 2.84-5.94). Americans of African origin, younger age, and higher CD4 count at AIDS diagnosis were also associated with acquiring an STD after AIDS. The number of people living with AIDS who acquired an STD increased over time from 60 (0.66%) in 1995 to 113 (1.32%) in 1998 (p<0.001). INTERPRETATION: We have shown that people on HAART are more likely to develop an STD, an epidemiological marker of unsafe sex. More intensive risk-reduction counselling and STD screening for people with AIDS is needed.

Linking clients from HIV antibody counseling and testing to prevention services.

The effectiveness of HIV antibody counseling and testing as a prevention intervention is limited: persons testing seronegative do not usually change their risk behaviors, some actually increase their risk behaviors, and decreases in risk behaviors are usually short-lived. Referrals to additional prevention and other needed services are therefore recommended, although the extent and determinants of referral provision for persons testing seronegative are unknown. We assessed the prevalence of referrals and the association between risk behaviors and prevention referrals among seronegatives. We reviewed HIV testing and referral data on all persons receiving confidential seronegative test results in San Francisco (SF) in the first 10 months of 1995 (n = 5,595), and gathered more detailed referral information at the municipal STD clinic from November 1995 through May 1996 (n = 747). The overall prevalence of referrals was low: a referral was given to 19.1% of the SF sample and 10.6% of the STD clinic sample; 15.4% of the SF sample and 5.9% of the STD clinic sample received a prevention referral. Injection drug users (IDUs) were the most likely to receive a prevention referral (48.5% of SF IDUs, 36.4% of STD clinic IDUs); men having sex with men and women with high-risk partners were also more likely to get a prevention referral than others. For SF IDUs, unsafe sex and needle sharing were not associated with an increased likelihood of receiving a prevention referral. Opportunities to link high-risk clients from counseling and testing to HIV prevention services are being missed. The referral component of HIV counseling and testing should be improved.

Soliton wavelength-division multiplexing system with channel-isolating notch filters.

We propose a wavelength-division multiplexing system in which transmission of solitons is stabilized by fixed- or sliding-frequency notch filters (a soliton rail), providing channel isolation. We demonstrate analytically and numerically that a soliton trapped in a channel between two notches is very robust. We also predict an optimum ratio between the channel separation and the soliton's spectral width. The effects of interchannel collisions are considered, and it is demonstrated that these effects can be largely eliminated by notch filters, which require a compensatory gain that is comparable with the basic gain balancing the fiber loss.

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.

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.

Use of antidiabetic and antihypertensive drugs in hospital and outpatient settings in Hong Kong.

OBJECTIVE: To investigate the usage patterns of antidiabetic and antihypertensive drugs and to identify any discordance between recommended management guidelines and clinical practice in two study locations. DESIGN: Prescription survey. SETTING: A government- operated general outpatient clinic (GOPC) and a medical/geriatric specialist clinic (SC) affiliated with a regional hospital in the same district. PATIENTS: Patients presenting with a prescription during the study period at the respective pharmacy were classified as having diabetes if at least one antidiabetic agent was prescribed and as having hypertension if a cardiovascular drug was prescribed in a hypotensive dosage. MAIN OUTCOME MEASURE: The pattern of use of antidiabetic and antihypertensive drugs. RESULTS: One thousand one hundred forty-four consecutive prescriptions were collected in the GOPC, and 1523 in the SC. Of 9.4% (n = 107) of patients were classified as having diabetes in the GOPC and 20.4% (n = 310) in the SC (p<0.001). Most patients with diabetes were taking oral hypoglycemic agents (98.1% in GOPC vs. 84.5% in SC). Glibenclamide was the sufonylurea used most often as monotherapy in both settings (50.5% in GOPC vs. 40.6% in SC). The combined use of a sulfonylurea with metformin was common in both settings (22.4% in GOPC vs. 28.4% in SC). Metformin monotherapy (1.9% in GOPC vs. 2.6% in SC) and combination treatment of insulin with an oral agent (0% in GOPC vs. 2.6% in SC) were rarely prescribed. In the GOPC, 24.5% (n = 280) of patients were prescribed an antihypertensive drug compared with 47.1% (n = 717) in the SC (p< 0.001). In the GOPC, the use of antihypertensive drugs was more prevalent in those with diabetes (53.5%) than in the remaining patients without diabetes (21.5%, p<0.001). In the SC, 51% of patients with diabetes were receiving antihypertensive drugs, but 40% of patients without diabetes were also receiving three treatments. In the GOPC, diuretics (indapamide 14.3% other 59%) and methyldopa (9.5%) were the most frequent choices of antihypertensive drugs when used as monotherapy in subjects without diabetes. In the SC, apart from diuretics (indapamide 12.9%, other 20.3%), beta-blockers (29%) also were prescribed frequently. If treated with only one antihypertensive drug, most patients with diabetes in the GOPC were prescribed indapamide (72.7%), and patients in the SC were treated mainly with angiotensin-converting enzyme inhibitors (35%) indapamide (22.5%), or calcium-channel blockers (13.8%). CONCLUSIONS: In this prescription-based survey, diabetes mellitus and hypertension were found to be common diseases in general practice and in a hospital SC. Oral hypoglycemic agents were the main from of antidiabetic therapy in both settings, with glibenclamide being the most commonly prescribed sulfonylurea. The types of antihypertensive drugs used were different in the two locations and varied according to the coexistence of type II diabetes mellitus. Despite some potential limitations, prescription-based surveys are an easy and economical method for surveying the occurrence of some common medical problems and the pattern of drug use in a fairly large number of patients in health institutions.

Nonlinear-optical amplifier based on a dual-core fiber.

We propose a scheme for all-optical amplification based on a nonlinear-optical coupler in which one core is amplifying while another is attenuating. In this scheme the input signal is fed into the amplifying core, from where the output is also obtained. A weak input easily couples to the lossy core and gets dissipated in it, whereas a stronger signal stays and undergoes a nearly linear amplification in the active core. When it is used for reshaping pulses in a long transmission line, this scheme should allow the pulses to be amplified while simultaneously suppressing the noises between them. Simulating equations for the cw signal in this model, we are able to find a regime that provides for a strong contrast between the suppression of weak signals and amplification of strong ones as well as a steep transition from suppression to amplification at a certainthreshold.

Time-domain soliton filter based on a semidissipative dual-core fiber.

We propose a time-domain dual-core fiber filter that greatly reduces soliton jitters and noise power in its application to ultrahigh-speed soliton communication systems. This filter is simply a dual-core fiber that has one core with negligible loss and the other with large loss.

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.

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.

Analytical solution to soliton switching in nonlinear twin-core fibers.

We give an approximate analytical solution to the coupled nonlinear Schrödinger equations that govern the soliton switching in a nonlinear fiber coupler. We have derived, in simple analytical form, the switching condition by which solitons can be switched from one core to another. The analytical result has been checked against the numerical results, and it is found that there is close agreement.

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.

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.

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.

Twin-core optical fiber with large core ellipticity.

The first (we believe) twin-core optical fiber with large core ellipticity has been fabricated, and its significant polarization dependent coupling properties have been demonstrated.