Radiosensitization of noradrenaline transporter-expressing tumour cells by proteasome inhibitors and the role of reactive oxygen species

Background The radiopharmaceutical 131I-metaiodobenzylguanidine (131I-MIBG) is used for the targeted radiotherapy of noradrenaline transporter (NAT)-expressing neuroblastoma. Enhancement of 131I-MIBG's efficacy is achieved by combination with the topoisomerase I inhibitor topotecan - currently being evaluated clinically. Proteasome activity affords resistance of tumour cells to radiation and topoisomerase inhibitors. Therefore, the proteasome inhibitor bortezomib was evaluated with respect to its cytotoxic potency as a single agent and in combination with 131I-MIBG and topotecan. Since elevated levels of reactive oxygen species (ROS) are induced by bortezomib, the role of ROS in tumour cell kill was determined following treatment with bortezomib or the alternative proteasome inhibitor, MG132.<p></p> Methods Clonogenic assay and growth of tumour xenografts were used to investigate the effects of proteasome inhibitors alone or in combination with radiation treatment. Synergistic interactions in vitro were evaluated by combination index analysis. The dependency of proteasome inhibitor-induced clonogenic kill on ROS generation was assessed using antioxidants.<p></p> Results Bortezomib, in the dose range 1 to 30 nM, decreased clonogenic survival of both SK-N-BE(2c) and UVW/NAT cells, and this was prevented by antioxidants. It also acted as a sensitizer in vitro when administered with X-radiation, with 131I-MIBG, or with 131I-MIBG and topotecan. Moreover, bortezomib enhanced the delay of the growth of human tumour xenografts in athymic mice when administered in combination with 131I-MIBG and topotecan. MG132 and bortezomib had similar radiosensitizing potency, but only bortezomib-induced cytotoxicity was ROS-dependent.<p></p> Conclusions Proteasome inhibition shows promise for the treatment of neuroblastoma in combination with 131I-MIBG and topotecan. Since the cytotoxicity of MG132, unlike that of bortezomib, was not ROS-dependent, the latter proteasome inhibitor may have a favourable toxicity profile in normal tissues.<p></p&gt

Time trends in survival and readmission following coronary artery bypass grafting in Scotland, 1981-96: retrospective observational study

Improvements in coronary revascularisation techniques and an increase in the use of percutaneous interventions1 have led to a rise in the number of coronary artery bypass grafting operations in older patients with more severe cardiac disease and worse comorbidity and who have previously undergone revascularisation procedures. 2 3 Advances in surgical and anaesthetic techniques have prevented a worsening risk profile from being translated into an increase in perioperative deaths. 2 3 The aim of our study was to examine time trends in major outcomes up to two years after coronary artery bypass grafting

Second Harmonic Generation for a Dilute Suspension of Coated Particles

We derive an expression for the effective second-harmonic coefficient of a dilute suspension of coated spherical particles. It is assumed that the coating material, but not the core or the host, has a nonlinear susceptibility for second-harmonic generation (SHG). The resulting compact expression shows the various factors affecting the effective SHG coefficient. The effective SHG per unit volume of nonlinear coating material is found to be greatly enhanced at certain frequencies, corresponding to the surface plasmon resonance of the coated particles. Similar expression is also derived for a dilute suspension of coated discs. For coating materials with third-harmonic (THG) coefficient, results for the effective THG coefficients are given for the cases of coated particles and coated discs.Comment: 11 pages, 3 figures; accepted for publication in Phys. Rev.

Dimensional Crossover in the Effective Second Harmonic Generation of Films of Random Dielectrics

The effective nonlinear response of films of random composites consisting of a binary composite with nonlinear particles randomly embedded in a linear host is theoretically and numerically studied. A theoretical expression for the effective second harmonic generation susceptibility, incorporating the thickness of the film, is obtained by combining a modified effective-medium approximation with the general expression for the effective second harmonic generation susceptibility in a composite. The validity of the thoretical results is tested against results obtained by numerical simulations on random resistor networks. Numerical results are found to be well described by our theory. The result implies that the effective-medium approximation provides a convenient way for the estimation of the nonlinear response in films of random dielectrics.Comment: 9 pages, 2 figures; accepted for publication in Phys. Rev.

CAPABLE trial: A randomized controlled trial of nurse, occupational therapist and handyman to reduce disability among older adults: Rationale and design

AbstractBackgroundAs the population ages, it is increasingly important to test new models of care that improve life quality and decrease health costs. This paper presents the rationale and design for a randomized clinical trial of a novel interdisciplinary program to reduce disability among low income older adults based on a previous pilot trial of the same design showing strong effect.MethodsThe CAPABLE (Community Aging in Place, Advancing Better Living for Elders) trial is a randomized controlled trial in which low income older adults with self-care disability are assigned to one of two groups: an interdisciplinary team of a nurse, occupational therapist, and handyman to address both personal and environmental risk factors for disability based on participants' functional goals, or an attention control of sedentary activities of choice. Both groups receive up to 10 home visits over 4months.OutcomesThe primary outcome is decreased disability in self-care (ADL). Secondary outcomes are sustained decrease in self care disability as well as improvement in instrumental ADLS, strength, balance, walking speed, and health care utilization. Careful cost tracking and analysis using intervention data and claims data will enable direct measurement of the cost impact of the CAPABLE approach. CAPABLE has the potential to leverage current health care spending in Medicaid waivers, Accountable Care Organizations and other capitated systems to save the health care system costs as well as improving low income older adults' ability to age at home with improved life quality

Size and frequency of natural forest disturbances and Amazon carbon balance

Forest inventory studies in the Amazon indicate a large terrestrial carbon sink. However, field plots may fail to represent forest mortality processes at landscape-scales of tropical forests. Here we characterize the frequency distribution of disturbance events in natural forests from 0.01 ha to 2,651 ha size throughout Amazonia using a novel combination of forest inventory, airborne lidar and satellite remote sensing data. We find that small-scale mortality events are responsible for aboveground biomass losses of B1.28 Pg C y 1 over the entire Amazon region. We also find that intermediate-scale disturbances account for losses of B0.01 Pg C y 1 , and that the largest-scale disturbances as a result of blow-downs only account for losses of B0.003 Pg C y 1 . Simulation of growth and mortality indicates that even when all carbon losses from intermediate and large-scale disturbances are considered, these are outweighed by the net biomass accumulation by tree growth, supporting the inference of an Amazon carbon sink

Fibrin glue obliteration is safe, effective and minimally invasive as first line treatment for pilonidal sinus disease in children

Background / Purpose: Sacrococcygeal pilonidal sinus disease (PSD) has an incidence of 1.2–2.5/1000 in children. Onset is around puberty. Symptoms of recurrent abscess and chronic suppuration may interfere with education and social integration. Treatments should cause minimal disruption while having good cure and recurrence rates. Curettage and Fibrin glue obliteration (FGO) show promising results in adults. We present our experience of its use in children.Methods: Review of all pediatric patients receiving FGO of pilonidal sinus performed by a single surgeon from September 2014 to February 2018.Results: Eighteen patients were identified. Median age was 16 (range 15–17), 55.6% were male. All procedures were completed as day cases. Median operative duration was 14 .1 (6–29) min. Twelve patients required only 1 procedure, 4 required 2 procedures, 1 required 5 procedures and 1 elected for formal excision after 2 FGO treatments. Median return to normal activities was 3 days, with 1 day school absence. Two patients developed minor surgical site infections. Median follow-up was 52 weeks (17–102), during which time there was 1 recurrence (5.6%).Conclusion: This study demonstrates FGO is a safe, effective procedure for pediatric PNS, with results comparable to off-midline flap techniques and without the need for extensive tissue excision and the associated morbidity

Asymptotic Fourier Coefficients for a C ∞ Bell (Smoothed-“Top-Hat”) & the Fourier Extension Problem

In constructing local Fourier bases and in solving differential equations with nonperiodic solutions through Fourier spectral algorithms, it is necessary to solve the Fourier Extension Problem. This is the task of extending a nonperiodic function, defined on an interval , to a function which is periodic on the larger interval . We derive the asymptotic Fourier coefficients for an infinitely differentiable function which is one on an interval , identically zero for , and varies smoothly in between. Such smoothed “top-hat” functions are “bells” in wavelet theory. Our bell is (for x ≥ 0) where where . By applying steepest descents to approximate the coefficient integrals in the limit of large degree j , we show that when the width L is fixed, the Fourier cosine coefficients a j of on are proportional to where Λ( j ) is an oscillatory factor of degree given in the text. We also show that to minimize error in a Fourier series truncated after the N th term, the width should be chosen to increase with N as . We derive similar asymptotics for the function f ( x )= x as extended by a more sophisticated scheme with overlapping bells; this gives an even faster rate of Fourier convergencePeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43417/1/10915_2005_Article_9010.pd

Modeling quark-hadron duality for relativistic, confined fermions

We discuss a model for the study of quark-hadron duality in inclusive electron scattering based on solving the Dirac equation numerically for a scalar confining linear potential and a vector color Coulomb potential. We qualitatively reproduce the features of quark-hadron duality for all potentials considered, and discuss similarities and differences to previous models that simplified the situation by treating either the quarks or all particles as scalars. We discuss the scaling results for PWIA and FSI, and the approach to scaling using the analog of the Callan-Gross relation for y-scaling.Comment: 38 pages, 21 figure

Single polynomials that correspond to pairs of cyclotomic polynomials with interlacing zeros

of cyclotomic polynomials with interlacing zero