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Background: The European Society of Medical Oncology (ESMO) has suggested using the ESMO-Magnitude of Clinical Benefit Scale (MCBS) to grade the magnitude of clinical benefit of cancer therapies. This approach has not been applied to radiation therapy (RT) yet. We applied the ESMO-MCBS to experiences describing the use of RT to assess (1) the 'scoreability' of the data, (2) evaluate the reasonableness of the grades for clinical benefit and (3) identify potential shortcomings in the current version of the ESMO-MCBS in its applicability to RT., Materials and Methods: We applied the ESMO-MCBS v1.1 to a selection of studies in radiotherapy that had been identified as references in the development of American Society for Radiation Oncology (ASTRO) evidence-based guidelines on whole breast radiation. Of the 112 cited references, we identified a subset of 16 studies that are amenable to grading using the ESMO-MCBS., Results: Of the 16 studies reviewed, 3/16 were scoreable with the ESMO tool. Six of 16 studies could not be scored because of shortcomings in the ESMO-MCBS v1.1: (1) in 'non-inferiority studies', there is no credit for improved patient convenience, reduced patient burden or improved cosmesis; (2) in 'superiority studies' evaluating local control as a primary endpoint, there is no credit for the clinical benefit such as reduced need for further interventions. In 7/16 studies, methodological deficiencies in the conduct and reporting were identified., Conclusions: This study represents a first step in determining the utility of the ESMO-MCBS in the evaluation of clinical benefit in radiotherapy. Important shortcomings were identified that would need to be addressed in developing a version of the ESMO-MCBS that can be robustly applied to radiotherapy treatments. Optimization of the ESMO-MCBS instrument will proceed to enable assessment of value in radiotherapy., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The relationship between the subcellular distribution of accumulated toxic metals into five operational fractions (subsequently combined into presumed detoxified and non-detoxified components) and toxicity in the clam Scrobicularia plana was investigated under different laboratory exposures. Clams were exposed to metal contaminated media (water and diet) and analysed for the partitioning of accumulated As, Cu and Zn into subcellular fractions. In general, metallothionein-like proteins, metal-rich granules and cellular debris in different proportions acted as main storage sites of accumulated metals in the clam soft tissues for these three metals. No significant differences were noted in the accumulation rates of As, Cu and Zn of groups of individuals with or without apparent signs of toxicity after up to 30 days of exposure to naturally contaminated sediment mixtures. There was, however, an increased proportional accumulation of Cu in the non-detoxified fraction with increased Cu accumulation rate in the clams, suggesting that the Cu uptake rate from contaminated sediments exceeded the combined rates of elimination and detoxification of Cu, with the subsequent likelihood for toxic effects in the clams., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The clonal expansion of effector T cells and subsequent generation of memory T cells are critical in determining the outcome of transplantation. While cytotoxic T lymphocytes induce direct cytolysis of target cells through secretion of Granzyme-B (GrB), they also express cytoplasmic serine protease inhibitor-6 (Spi6) to protect themselves from GrB that has leaked from granules. Here, we studied the role of GrB/Spi6 axis in determining clonal expansion of alloreactive CD8-T cells and subsequent generation of memory CD8-T cells in transplantation. CD8-T cells from Spi6(-/-) mice underwent more GrB mediated apoptosis upon alloantigen stimulation in vitro and in vivo following adoptive transfer into an allogeneic host. Interestingly, while OT1.Spi6(-/-) CD8 T cells showed significantly lower clonal expansion following skin transplants from OVA mice, there was no difference in the size of the effector memory CD8-T cells long after transplantation. Furthermore, lack of Spi6 resulted in a decrease of short-lived-effector-CD8-cells but did not impact the pool of memory-precursor-effector-CD8-cells. Similar results were found in heart transplant models. Our findings suggest that the final alloreactive CD8-memory-pool-size is independent from the initial clonal-proliferation as memory precursors express low levels of GrB and therefore are independent of Spi6 for survival. These data advance our understanding of memory T cells generation in transplantation and provide basis for Spi6 based strategies to target effector T cells., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The fouling barnacle Amphibalanus amphitrite is a cosmopolitan biomonitor of trace metal bioavailabilities, with an international comparative data set of body metal concentrations. Bioavailabilities of As, Cd, Cr, Cu, Fe, Mn, Pb, V and Zn to A. amphitrite were investigated at 19 sites along the Iranian coast of the understudied Persian Gulf. Commercial and fishing ports showed extremely high Cu bioavailabilities, associated with high Zn bioavailabilities, possibly from antifouling paints and procedures. V availability was raised at one port, perhaps associated with fuel leakage. Cd bioavailabilities were raised at sites near the Strait of Hormuz, perhaps affected by adjacent upwelling off Oman. The As data allow a reinterpretation of the typical range of accumulated As concentrations in A. amphitrite. The Persian Gulf data add a new region to the A. amphitrite database, confirming its importance in assessing the ecotoxicologically significant trace metal contamination of coastal waters across the world., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Many estuaries of southwest England were heavily contaminated with toxic metals associated with the mining of copper and other metals, particularly between 1850 and 1900. The question remains whether the passage of time has brought remediation to these estuaries. In 2003 and 2006 we revisited sites in 5 metal-contaminated estuaries sampled in the 1970s and 1980s - Restronguet Creek, Gannel, West Looe, East Looe and Tavy. We evaluate changes in metal contamination in sediments and in metal bioavailabilities in sediments and water to local organisms employed as biomonitors. We find that the decline in contamination in these estuaries is complex. Differences in bioavailable contamination in the water column were detectable, as were significant detectable changes in at least some estuaries in bioavailable metal contamination originating from sediments. However, in the 100 years since mining activities declined, bioavailable contamination has not declined to the regional baseline in any estuary affected by the mine wastes. The greatest decline in contamination occurred in the one instance (East Looe) where a previous industrial source of (Ag) contamination was considered. We used the macroalgae Fucus vesiculosus and Ascophyllum nodosum as biomonitors of dissolved metal bioavailabilities and the deposit feeders Nereis diversicolor and Scrobicularia plana as biomonitors of bioavailable metal in sediments. We found no systematic decrease in the atypically high Ag, Cu, Pb and Zn concentrations in the estuarine sediments over a 26 year period. Accumulated metal (Ag, As, Cu, Pb, and Zn) concentrations in the deposit feeders are similarly still atypically high in at least one estuary for each metal, and there is no consistent evidence for general decreases in sediment metal bioavailabilities over time. We conclude that the legacy of mining in sheltered estuaries of southwest England is the ongoing presence of sediments rich in metals bioavailable to deposit feeders, while dissolved metal bioavailabilities from this historical source alone are no longer atypically high., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Biodynamic parameters of the ragworm Nereis diversicolor from southern Spain and south England were experimentally derived to assess the inter-population variability of physiological parameters of the bioaccumulation of Ag, Cd and Zn from water and sediment. Although there were some limited variations, these were not consistent with the local metal bioavailability nor with temperature changes. Incorporating the biodynamic parameters into a defined biodynamic model, confirmed that sediment is the predominant source of Cd and Zn accumulated by the worms, accounting in each case for 99% of the overall accumulated metals, whereas the contribution of dissolved Ag to the total accumulated by the worm increased from about 27 to about 53% with increasing dissolved Ag concentration. Standardised values of metal-specific parameters were chosen to generate a generalised model to be extended to N. diversicolor populations across a wide geographical range from western Europe to North Africa. According to the assumptions of this model, predicted steady state concentrations of Cd and Zn in N. diversicolor were overestimated, those of Ag underestimated, but still comparable to independent field measurements. We conclude that species-specific physiological metal bioaccumulation parameters are relatively constant over large geographical distances, and a single generalised biodynamic model does have potential to predict accumulated Ag, Cd and Zn concentrations in this polychaete from a single sediment metal concentration.

The amphipod crustacean Talitrus saltator is an established, easily accessible, biomonitor of trace metal bioavailabilities in coastal waters. We have carried out a geographically widespread collection of T. saltator from European shores, stretching from the north-west Atlantic through the Baltic to the Mediterranean. A primary aim of the work was to establish a database of accumulated trace metal concentrations (Cd, Cr, Cu, Fe, Mn and Zn) in this biomonitor. Statistical analysis has shown significant geographical differences in the bioavailabilities of all the metals, the most distinct being copper, iron and manganese. It has proved possible to identify unusually high accumulated concentrations of Cd, Cr, Cu, Fe, Mn and Zn in this biomonitor, indicative of high metal bioavailability at a particular site. These may serve as reference points for future biomonitoring programmes seeking to identify metal contamination in coastal waters.

Changes in salinity affect the bioavailability and consequent uptake of trace metals by euryhaline invertebrates. In many cases, salinity-related effects on metal uptake can be explained by changes in chemical speciation but salinity may also influence uptake indirectly through its action on osmoregulatory mechanisms. Specifically, it can be hypothesised that trace metal uptake may be reduced at salinities approaching the isosmotic point of a species because, at this point, there is reduced activity of ionic exchange pumps. The present study tested this hypothesis using the Chinese mitten crab, Eriocheir sinensis, a hyper-hypoosmoregulator with an isosmotic point around 33 per thousand. Crabs were exposed to radio-labelled cadmium and zinc at 23, 33 and 43 per thousand for 4 days. To eradicate speciation effects, crabs were exposed to the same concentration of the radio-labelled free metal ion (estimated using MineQL computer software) at each salinity. Haemolymph samples were taken daily and radio-labelled metal concentrations were estimated from radioactivity counts and used to provide relative measures of metal uptake. Neither cadmium nor zinc uptake was lowest at the isosmotic point. The uptake of cadmium increased significantly with increase in salinity, while the uptake of zinc showed no significant change with increased salinity. Thus changes in trace metal uptake rates in E. sinensis do not appear to be controlled only by changes in free metal ion concentrations. The different effects of salinity change on the uptake of cadmium and zinc (in the absence of free metal ion change) also indicate that physiological responses to osmotic change alone do not control metal uptake rates for this species.

Transforming growth factor beta (TGF-beta) stimulates protein complex formation on a TGF-beta response element (TAE) found in the distal portion (-1624) of the collagen alpha 1(I) promoter. To identify the fibroblast proteins in this complex, an expression library constructed from human embryonic lung fibroblasts mRNA was screened using a tetramer of TAE. Y-box binding protein (YB-1), was identified as a protein in the TAE-protein complex. The protein expressed by phage clones formed a specific complex with labeled TAE but not mutated TAE (mTAE) similar to the complex formed with nuclear protein. Nuclear protein-TAE complexes isolated from native gels contained YB-1 by Western analysis. TGF-beta treatment increased the amount of YB-1 protein in nuclear extracts, decreased its amount in cytoplasm, but did not alter the steady state levels of YB-1 mRNA. A full-length YB-1 protein expressed in human lung fibroblasts was primarily located in the nucleus with punctate staining in cytoplasmic regions. The expression of YB-1 decreased in the cytoplasm after 2 h of TGF-beta treatment. Therefore, the increased binding activity seen in TGF-beta-stimulated nuclear extracts was due primarily to relocalization of YB-1 from the cytoplasm to the nuclear compartment. Co-transfection of YB-1 cDNA with a collagen promoter-reporter construct caused a dose-dependent activation of collagen promoter activity in rat fibroblasts whereas the promoter with a mutation in the TAE element was not sensitive to YB-1 co-expression. In conclusion, we have identified YB-1 as a protein that interacts with a TGF-beta response element in the distal region of the collagen alpha 1(I) gene. YB-1 protein activates the collagen promoter and translocates into the nucleus during TGF-beta addition to fibroblasts, suggesting a role for this protein in TGF-beta signaling.

Internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 have been found in 20% to 30% of patients with acute myeloid leukemia (AML). These mutations constitutively activate the receptor and appear to be associated with a poor prognosis. Recent evidence that this constitutive activation is leukemogenic renders this receptor a potential target for specific therapy. In this study, dose-response cytotoxic assays were performed with AG1295, a tyrosine kinase inhibitor active against FLT3, on primary blasts from patients with AML. For each patient sample, the degree of cytotoxicity induced by AG1295 was compared to the response to cytosine arabinoside (Ara C) and correlated with the presence or absence of a FLT3/ITD mutation. AG1295 was specifically cytotoxic to AML blasts harboring FLT3/ITD mutations. The results suggest that these mutations contribute to the leukemic process and that the FLT3 receptor represents a therapeutic target in AML. (Blood. 2001;98:885-887)

Arousal and anxiety responses to stressful stimulation are products of multiple factors that may include the physiological, behavioral, cognitive, affective, trait, and state components of our six-system model, as well as mediational and non-mediational perspectives. Within the context of this model, the present experiment examined the effects of prior exposure to neutral stimuli on arousal and anxiety responses to stress. High and low trait-anxious participants were randomly assigned to one of three prior exposure conditions in which they were exposed to stressful stimuli following exposure to: (a) neutral, non-stressful stimulation in the same modality (the Intramodality Prior Exposure or IPE experimental condition); (b) neutral stimuli in a different modality (the Cross-modality Prior Exposure or CPE control condition); or (c) a rest period (the Stress Only or SO control condition). Results showed that low trait anxious subjects had consistently larger arousal and anxiety responses to stress than did highs and that prior exposure to certain same-modality neutral stimuli reduced responses to subsequent stressors. In addition, arousal was greater in response to cognitive than to affective and in response to non-mediational than mediational conditions. Results are discussed in terms of the inverted-U arousal function and of the six-system model and its implications for understanding anxiety and arousal.

The authors conducted a randomized, double-blind, 10-week clinical trial of two doses of nortriptyline in eight nursing homes. Sixty-nine patients, average age 79.5 years, were randomized to receive regular doses (60 mg-80 mg/day) vs. low doses (10 mg-13 mg/day) of nortriptyline. Among the more cognitively intact patients, there was a significant quadratic relationship defining a "therapeutic window" for nortriptyline plasma levels and clinical improvement. There were also significant differences in plasma level-response relationships between depressed patients who were cognitively impaired and those who were more cognitively intact. Depression remains a syndrome that responds to specific treatment, even in frail nursing home patients, and those depressions that occur in patients with significant dementia may represent a treatment-relevant condition with a different plasma level-response relationship than in depression alone.

Studies have demonstrated that the selective serotonin reuptake inhibitor antidepressants have similar efficacy to other agents, such as tricyclic antidepressants. However, data are limited for direct comparisons with other antidepressants. The authors conducted a contemporaneous comparison of nursing home residents treated with open-label sertraline in doses up to 100 mg/day with nursing home residents treated in a double-blind randomized study of low vs. regular doses of nortriptyline. There were 97 patients enrolled in the study (28 treated with sertraline), with an average treatment duration of 55 days. There were no differences in the tolerability of sertraline vs. nortriptyline. However, in this group of frail older adults, sertraline was not as effective as nortriptyline for the treatment of depression.

The present experiment was a test of a new six-system model of anxiety, which includes physiological, behavioral, cognitive, affective, trait, and state components of anxiety and also differentiates between direct and mediated responses. The State-Trait Anxiety Inventory was used to screen 795 undergraduates at the University of Maryland. Of the 52 subjects chosen, half were high trait anxious and half low. The two groups were further divided into high and low situational stress conditions. Subjects in the high-stress condition were exposed to two types of stressful cognitive and two types of stressful affective tasks. Subjects in the low-stress condition were exposed to the same four tasks with the stressful aspect removed. Prior state anxiety and cognitive or affective sensitivity were also considered. It was found that the most influential factor in resultant arousal was situational stress. Trait anxiety, state anxiety, and cognitive vs. affective sensitivity also significantly influenced both direct and mediated physiological and subjective anxiety responses. In addition, rather than leading to increased arousal, as hypothesized, the presence of trait and state anxiety reduced arousal under certain conditions.

Hereditary stomatocytosis is a red cell membrane protein disorder, which results in hemolytic anemia. Some patients with hereditary stomatocytosis experience dyspnea, chest pain, and abdominal pain, particularly after splenectomy. These symptoms may represent vaso-occlusion secondary to adherence of an abnormal erythrocyte membrane to vascular endothelium. We studied three members of a family with varying clinical expression of hereditary stomatocytosis. Adherence of red cells to endothelium was quantified by measuring the shear force required to separate individual cells from endothelial monolayers using a micropipette technique. Two patients with symptoms of in situ thromboses had a higher percentage of adherent cells compared with their asymptomatic sibling and normal controls. Correlation between this in vitro phenomenon and the clinical course suggests that flow abnormalities in the microcirculation attributable to erythrocyte endothelial adherence may play an important pathogenetic role in the illness. When the proportion of adherent red cells was reduced by a chronic transfusion program in one patient and pentoxifyllin therapy in another, the vaso-occlusive complications were eliminated.

Objectives: Our purpose was to assess the potential for an external vaginal antiitch cream (20% benzocaine, 3% resorcinol) to significantly increase levels of methemoglobin above normal in healthy women., Study Design: Fifty-five women reporting external vaginal itch were recruited for the study. Each patient was used as her own control with methemoglobin levels being measured before and after use of the cream. Women were instructed to apply a 1-inch strip of cream by fingertip to the external genital area three or four times a day for 7 consecutive days., Results: There were no significant differences in methemoglobin levels before and after use or in levels from a subgroup of women aged > 50 years compared with levels in a younger population., Conclusions: This preparation appears to be safe when used as directed; however, the results cannot be extrapolated to the very young. Nevertheless, lavish or frequent application over wide areas of excoriation might lead to toxic concentrations and methemoglobinemia. Therefore patients with serious vaginal disease should be advised against self-treatment beyond the 7-day limit imposed by the Food and Drug Administration for over-the-counter external analgesic medications.

Boronic acids were found to facilitate the transport of various ribonucleosides in and out of liposomes (artificial cells). Most experiments were conducted with large unilamellar vesicles composed of dipalmitoylphosphatidyl choline, cholesterol, and phosphatidic acid in the ratio 20:15:2. Rates of nucleoside efflux were determined by a UV assay, whereas the influx experiments used a radiotracer method. Five boronic acids were studied: 3,5-bis(trifluoromethyl)phenylboronic acid (1), 3,5-dichlorophenylboronic acid (2), 4-tert-butylphenylboronic acid (3), 1-butylboronic acid (4), and 4-carboxyphenylboronic acid (5). The order of carrier effectiveness was found to be 1 > 3 > 2 >> 4 >> 5. Efflux and influx experiments with mixtures of nucleosides and sucrose showed virtually complete transport selectivity in favor of the nucleosides. Mechanistic studies indicate that the nucleoside transport mechanism involves transient formation of a lipophilic, trigonal boronate ester.

A chemically transformed cell line, W8, produces alpha 1(I) homotrimers with no alpha 2(I) chains whereas the parent cell line, K16, produces heterotrimers. When W8 cells were transfected with plasmid constructs containing the full length human alpha 2(I) cDNA driven by viral promoters, the cells expressed alpha 2(I) collagen chains forming varying amounts of heterotrimers. Previously, we have shown that K16 and W8 cells have different growth characteristics (Smith, B.D. et al., Cancer Research 43: 4275-4282, 1983) including population doubling, saturation density, cell adhesion and colony formation in soft agar. These parameters were tested for each transfected cell line in order to determine if the alpha 2(I) expression and heterotrimer formation alters cell characteristics. The cells expressing alpha 2(I) forming heterotrimers needed higher concentrations of trypsin or longer time periods to lift from the plate suggesting a role for alpha 2(I) in cell adhesion. The W8 cells formed colonies in soft agar exhibiting anchorage independent growth. However, W8 cells expressing alpha 2(I) chains formed less colonies in soft agar than W8 cells or W8 cells transfected with a neomycin resistant gene indicating that the alpha 2(I) producing cells were less anchorage independent than W8 cells. Population doubling time, morphology and saturation densities were similar to W8 cells with small alterations towards an epithelial morphology. These results demonstrated that alpha 2(I) within heterotrimer is important for cell adhesion and anchorage independent growth.

Although a number of studies support an arousal theory interpretation of differential sensation-seeking behavior, the conditions under which arousal correlates of this personality dimension are manifest is as yet unclear. Both theory and research suggest that among the external factors affecting the differential arousal response are stimulus relevance and stimulus intensity. The present study assessed the impact of these factors on both psychophysiological and behavioral responses. Subjects were preselected to represent the extremes of the sensation-seeking dimension, then exposed to auditory and visual presentations of a series of sexual and aggressive stimuli of systematically varied intensity. High sensation seekers gave larger amplitude SCRs to violent stimuli and larger initial responses to sexual stimuli presented visually, while verbal response intensities showed an opposite pattern. Overall, results provided support for an arousal theory interpretation of sensation-seeking, but suggested that the probability and magnitude of group differences is a somewhat complex function of stimulus intensity, stimulus modality, and perhaps other factors not yet assessed.

This paper presents a three-dimensional convolution formula for a general set of cone beam data. This formula is illustrated by examining at length the formula for a particular set of cone beam data--the set of cone beam data from source points which are located along a straight line. How the three-dimensional formula could be implemented for a general set of cone data is discussed.

Reduction of pH over the range 6.0-4.5 results in a decrease of erythrocyte deformability in parallel with the induced progressive sphericity of cells. At low deformation rates employed, increase of hemoglobin viscosity was not significant. A decrease of membrane elasticity was detected in cells when sphering, the major determinant of cellular deformability, was prevented at pH 5.0 by hyperosmotic medium. The pronounced change of deformability and the reduced elasticity occurred at calculated intracellular pH values at which solubility in vitro of extracted erythrocyte spectrin is also markedly reduced. The parallel decrease of deformability and spectrin solubility supports the hypothesis that spectrin aggregation may contribute to regulation of erythrocyte deformability through effects on shape and membrane elastic characteristics.

Detachment of individual sickle erythrocytes from cultured endothelial cell monolayers has been evaluated by a fluid-shearing technique in an effort to quantitate adherence at shear forces that would be anticipated in the in vivo circulation. Nonirreversibly sickled cells (non-ISC) were more adherent at normal oxygen tensions than control cells. More than 1% non-ISC remained attached to the monolayer at forces greater than physiologic shear stresses in capillary and venous circulations, and many of the most avidly attached cells, once separated, immediately reattached to adjacent endothelial cells. These data suggest that hemoglobin S-containing erythrocytes may have a higher frequency of adherence in vivo in regions of low shear stress where prolonged erythrocyte-endothelial cell contact could occur. Some of these cells detached by shear force would subsequently reattach in in vivo conditions. Plasma-enhanced attachment frequency and plasma from blood in a case of sickle crisis caused further increase. These observations further support the concept that sickle erythrocyte-endothelial cell interaction may be a significant factor in initiation of vascular occlusive events in sickle cell disease.