Preferences of German and Swiss melanoma patients for toxicities versus melanoma recurrence during adjuvant treatment (GERMELATOX-A-trial).

PURPOSE: Adjuvant treatment with immune checkpoint inhibitors like PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT) in high-risk melanoma patients demonstrate a significant improvement in disease-free survival (DFS). Due to specific side effects, the choice of treatment is very often driven by the risk for toxicity. This study addressed for the first time in a multicenter setting the attitudes and preferences of melanoma patients for adjuvant treatment with (c)ICI and TT. METHODS: In this study ("GERMELATOX-A"), 136 low-risk melanoma patients from 11 skin cancer centers were asked to rate side effect scenarios typical for each (c)ICI and TT with mild-to-moderate or severe toxicity and melanoma recurrence leading to cancer death. We asked patients about the reduction in melanoma relapse and the survival increase at 5 years they would require to tolerate defined side-effects. RESULTS: By VAS, patients on average valued melanoma relapse worse than all scenarios of side-effects during treatment with (c)ICI or TT. In case of severe side effects, patients required a 15% higher rate of DFS at 5 years for (c)ICI (80%) compared to TT (65%). For survival, patients required an increase of 5-10% for melanoma survival during (c)ICI (85%/80%) compared to TT (75%). CONCLUSION: Our study demonstrated a pronounced variation of patient preferences for toxicity and outcomes and a clear preference for TT. As adjuvant melanoma treatment with (c)ICI and TT will be increasingly implemented in earlier stages, precise knowledge of the patient perspective can be helpful for decision making.

Expanding ecological assessment by integrating microorganisms into routine freshwater biomonitoring.

Bioindication has become an indispensable part of water quality monitoring in most countries of the world, with the presence and abundance of bioindicator taxa, mostly multicellular eukaryotes, used for biotic indices. In contrast, microbes (bacteria, archaea and protists) are seldom used as bioindicators in routine assessments, although they have been recognized for their importance in environmental processes. Recently, the use of molecular methods has revealed unexpected diversity within known functional groups and novel metabolic pathways that are particularly important in energy and nutrient cycling. In various habitats, microbial communities respond to eutrophication, metals, and natural or anthropogenic organic pollutants through changes in diversity and function. In this review, we evaluated the common trends in these changes, documenting that they have value as bioindicators and can be used not only for monitoring but also for improving our understanding of the major processes in lotic and lentic environments. Current knowledge provides a solid foundation for exploiting microbial taxa, community structures and diversity, as well as functional genes, in novel monitoring programs. These microbial community measures can also be combined into biotic indices, improving the resolution of individual bioindicators. Here, we assess particular molecular approaches complemented by advanced bioinformatic analysis, as these are the most promising with respect to detailed bioindication value. We conclude that microbial community dynamics are a missing link important for our understanding of rapid changes in the structure and function of aquatic ecosystems, and should be addressed in the future environmental monitoring of freshwater ecosystems.

Salivary but not plasma cortisone tracks the plasma cortisol response to exercise: effect of time of day.

INTRODUCTION: The cortisol, cortisone, corticosterone, and CBG responses to exercise in the AM and PM have not been described. This study examined the response of these glucocorticoids and CBG to intense exercise in 12 endurance-trained men in plasma (Pl) and saliva (Sa). METHODS: Each subject completed treadmill exercise in the morning and evening. Paired blood and Sa samples were obtained at rest before and after exercise. RESULTS: Significant time effect existed for Pl-cortisol and Sa-cortisol from baseline in the AM and PM (p < 0.01). Pl-cortisone and CBG significantly increased in the PM (p < 0.01). Pl-corticosterone increased in the AM and PM (p < 0.01). Unlike Pl-cortisone, Sa-cortisone was significantly higher in the AM compared to the PM, increasing in the AM and PM (All p < 0.01). Strong associations were found between Pl-cortisol and Sa-cortisol (r = 0.81, p < 0.0001), Pl-cortisol and Sa-cortisone (r = 0.81, p < 0.0001). CONCLUSIONS: (1) Intense EX induces a similar increase in Pl-cortisone (~90 %) and corticosterone (~200 %) in the AM and PM, whereas exercise increases CBG in the PM, but not in the AM; (2) vigorous exercise increases Sa-cortisone; (3) Sa-cortisone and cortisol are equally strongly correlated to Pl-cortisol, suggesting a significant role for Sa-cortisone as a novel marker of free cortisol during exercise.

ABH-Glycan Microarray Characterizes ABO Subtype Antibodies: Fine Specificity of Immune Tolerance After ABO-Incompatible Transplantation.

Organ transplantation from ABO blood group-incompatible (ABOi) donors requires accurate detection, effective removal and subsequent surveillance of antidonor antibodies. Because ABH antigen subtypes are expressed differently in various cells and organs, measurement of antibodies specific for the antigen subtypes in the graft is essential. Erythrocyte agglutination, the century-old assay used clinically, does not discriminate subtype-specific ABO antibodies and provides limited information on antibody isotypes. We designed and created an ABO-glycan microarray and demonstrated the precise assessment of both the presence and, importantly, the absence of donor-specific antibodies in an international study of pediatric heart transplant patients. Specific IgM, IgG, and IgA isotype antibodies to nonself ABH subtypes were detected in control participants and recipients of ABO-compatible transplants. Conversely, in children who received ABOi transplants, antibodies specific for A subtype II and/or B subtype II antigens-the only ABH antigen subtypes expressed in heart tissue-were absent, demonstrating the fine specificity of B cell tolerance to donor/graft blood group antigens. In contrast to the hemagglutination assay, the ABO-glycan microarray allows detailed characterization of donor-specific antibodies necessary for effective transplant management, representing a major step forward in precise ABO antibody detection.

Structural evolution of Ag-Cu nano-alloys confined between AlN nano-layers upon fast heating.

The structural evolution of a Ag-Cu/AlN nano-multilayer (NML), as prepared by magnetron-sputtering on a α-Al2O3 substrate, was monitored during fast heating by real-time in situ XRD analysis (at the synchrotron), as well as by ex situ microstructural analysis using SEM, XPS and in-house XRD. The as-deposited NML is constituted of alternating nano-layers (thickness ≈ 10 nm) of a chemically inert AlN barrier and a eutectic Ag-Cu(40at%) nano-alloy. The nano-alloy in the as-deposited state is composed of a fcc matrix of Ag nano-grains (≈6 nm), which are supersaturated by Cu, and some smaller embedded Cu rich nano-grains (≈4 nm). Heating up to 265 °C activates segregation of Cu out of the supersaturated Ag nano-grains phase, thus initiating phase separation. At T > 265 °C, the phase-separated Cu metal partially migrates to the top NML surface, thereby relaxing thermally-accumulated compressive stresses in the confined alloy nano-layers and facilitating grain coarsening of (still confined) phase-separated nano-crystallites. Further heating and annealing up to 420 °C results in complete phase separation, forming extended Ag and Cu domains with well-defined coherent Ag/AlN interfaces. The observed outflow of Cu well below the eutectic melting point of the bulk Ag-Cu alloy might provide new pathways for designing low-temperature nano-structured brazing materials.

Spontaneous acetylcholine secretion from developing growth cones of Drosophila central neurons in culture: effects of cAMP-pathway mutations.

We describe a novel bioassay system that uses Xenopus embryonic myocytes (myoballs) to detect the release of acetylcholine from Drosophila CNS neurons. When a voltage-clamped Xenopus myoball was manipulated into contact with cultured Drosophila "giant" neurons, spontaneous synaptic current-like events were registered. These events were observed within seconds after contact and were blocked by curare and alpha-bungarotoxin, but not by TTX and Cd(2+), suggesting that they are caused by the spontaneous quantal release of acetylcholine (ACh). The secretion occurred not only at the growth cone, but also along the neurite and at the soma, with significantly different release parameters among various regions. The amplitude of these currents displayed a skewed distribution. These features are distinct from synaptic transmission at more mature synapses or autapses formed in this culture system and are reminiscent of the transmitter release process during early development in other preparations. The usefulness of this coculture system in studying presynaptic secretion mechanisms is illustrated by a series of studies on the cAMP pathway mutations, dunce (dnc) and PKA-RI, which disrupt a cAMP-specific phosphodiesterase and the regulatory subunit of cAMP-dependent protein kinase A, respectively. We found that these mutations affected the ACh current kinetics, but not the quantal ACh packet, and that the release frequency was greatly enhanced by repetitive neuronal activity in dnc, but not wild-type, growth cones. These results suggest that the cAMP pathway plays an important role in the activity-dependent regulation of transmitter release not only in mature synapses as previously shown, but also in developing nerve terminals before synaptogenesis.

An anteroposterior Dorsal gradient in the Drosophila embryo.

Dorsoventral (DV) patterning of the Drosophila embryo is initiated by a broad Dorsal (Dl) nuclear gradient, which is regulated by a conserved signaling pathway that includes the Toll receptor and Pelle kinase. We investigate the consequences of expressing a constitutively activated form of the Toll receptor, Toll(10b), in anterior regions of the early embryo using the bicoid 3' UTR. Localized Toll(10b) products result in the formation of an ectopic, anteroposterior (AP) Dl nuclear gradient along the length of the embryo. The analysis of both authentic dorsal target genes and defined synthetic promoters suggests that the ectopic gradient is sufficient to generate the full repertory of DV patterning responses along the AP axis of the embryo. For example, mesoderm determinants are activated in the anterior third of the embryo, whereas neurogenic genes are expressed in central regions. These results raise the possibility that Toll signaling components diffuse in the plasma membrane or syncytial cytoplasm of the early embryo. This study also provides evidence that neurogenic repressors may be important for the establishment of the sharp mesoderm/neuroectoderm boundary in the early embryo.

Beliefs about social integration from the perspectives of persons with mental retardation, job coaches, and employers.

Beliefs of multiple stakeholders who were all part of the same "transition community" (including persons with mental retardation, job coaches, and employers) about social integration outcomes and interventions in employment settings were examined. Data were collected through interviews and questionnaires that were designed based on a previously affirmed conceptual framework of social integration. Although results showed that stakeholders agreed on some outcomes and interventions they disagreed on others. These disagreements could be cause for concern because contrasting belief systems among stakeholders supposedly working toward the same goal might interfere with successful social integration in work settings for persons with mental retardation.

Regulation of a dpp target gene in the Drosophila embryo.

In Drosophila, two TGF-beta growth factors, dpp and screw, function synergistically to subdivide the dorsal ectoderm into two embryonic tissues, the amnioserosa and dorsal epidermis. Previous studies have shown that peak dpp activity is required for the localized expression of zerknüllt (zen), which encodes a homeodomain transcription factor. We present evidence that zen directly activates the amnioserosa-specific expression of a downstream target gene, Race (Related to angiotensin converting enzyme). A 533 bp enhancer from the Race promoter region is shown to mediate selective expression in the amnioserosa, as well as the anterior and posterior midgut rudiments. This enhancer contains three zen protein binding sites, and mutations in these sites virtually abolish the expression of an otherwise normal Race-lacZ fusion gene in the amnioserosa, but not in the gut. Genetic epistasis experiments suggest that zen is not the sole activator of Race, although a hyperactivated form of zen (a zen-VP16 fusion protein) can partially complement reduced levels of dpp activity. These results suggest that dpp regulates multiple transcription factors, which function synergistically to specify the amnioserosa.

Threshold responses to the dorsal regulatory gradient and the subdivision of primary tissue territories in the Drosophila embryo.

Dorsoventral patterning in Drosophila is initiated by the maternal regulatory factor dorsal (dl), which is a member of the Rel family of transcription factors. dl functions as a transcriptional activator and repressor to establish different territories of gene expression in the precellular embryo. Differential regulation of dl target genes may be essential for subdividing each tissue territory (the presumptive mesoderm, neuroectoderm, and dorsal ectoderm) into multiple cell types in older embryos. Different patterns of snail (sna) and decapentaplegic (dpp) expression help define the limits of inductive interactions between the mesoderm and dorsal ectoderm after gastrulation. Similarly, the differential regulation of short gastrulation (sog) and dpp may be decisive in the initial subdivision of the dorsal ectoderm, whereas different limits of gene expression within the neuroectoderm might provide the basis for the subsequent subdivision of this tissue into ventral and lateral regions.

Analysis of directions, responses, and consequences involving persons with mental retardation in employment and vocational training settings.

Parameters of direction-relevant stimuli (i.e., directness, complexity), types of responses, and consequences occurring in competitive worksites were compared with those in community vocational training sites. Direction sequences initiated by co-workers to 8 individuals with mental retardation were compared to those initiated by school personnel to 8 special education students in community-based vocational training. Results indicated that the majority of directions in either setting were direct/noncomplex; however, more indirect commands occurred in the employment setting. The types of responses to directions were proportionately similar in both groups. Only rarely were consequences contingent upon responses or lack thereof, particularly in the employment setting.

Regulation of the dorsal morphogen by the Toll and torso signaling pathways: a receptor tyrosine kinase selectively masks transcriptional repression.

The dorsal (dl) nuclear gradient initiates the differentiation of the mesoderm, neuroectoderm, and dorsal ectoderm by activating and repressing gene expression in the early Drosophila embryo. This gradient is organized by a Toll signaling pathway that shares many common features with the mammalian IL-1 cytokine pathway. Here we present evidence that a second signaling pathway, controlled by the torso (tor) receptor tyrosine kinase, also modulates dl activity. Evidence is presented that the tor pathway selectively masks the ability of dl to repress gene expression but has only a slight effect on activation. Intracellular kinases that are thought to function downstream of tor, such as D-raf and the rolled MAP kinase, mediate this selective block in repression. Normally, the Toll and tor pathways are both active only at the embryonic poles, and consequently, target genes (zen and dpp) that are repressed in middle body regions are expressed at these sites. Constitutive activation of the tor pathway causes severe embryonic defects, including disruptions in gastrulation and mesoderm differentiation, as a result of misregulation of dl target genes. These results suggest that RTK signaling pathways can control gene expression by antirepression, and that multiple pathways can fine-tune the activities of a single transcription factor.

Assessing the loneliness of workers with mental retardation.

This study was designed to determine whether a reliable instrument could be developed to measure the loneliness experienced by workers with mental retardation. In addition, supervisors were asked to rate subjects on loneliness and four other behavioral subtypes in order to determine whether there was a relation between these ratings and the loneliness questionnaire. Three groups of subjects were assessed: persons with mild, moderate, and severe mental retardation. Results indicated that the Worker Loneliness Questionnaire was a reliable instrument for use with persons with mild and moderate mental retardation. In addition, the results showed that some individuals were lonely; however, this was not a pervasive feeling. The implications for measuring the self-perceptions of individuals with mental retardation were discussed.

Toward defining and measuring social skills in employment settings.

Although it is clear that appropriate social skills are related to job success, little agreement has been reached on how to define and measure social skills. In this article a definition of social skills was proposed that will begin to identify the components that need to be considered when teaching social skills to individuals with mental retardation in employment settings. In addition, three measurement approaches were discussed that further operationalize these components. Current social skills training research in employment settings was reviewed and discussed with respect to the measurement approaches proposed in this article.

Social ecology of the workplace: contextual variables affecting social interactions of employees with and without mental retardation.

The social interaction patterns of employees with and without mental retardation across several different competitive employment sites were observed directly; narrative recording procedures were used. The data were analyzed to determine whether there were differences between the two groups of employees and the people involved in the interactions and the time period of the interaction and whether the interaction involved a social or task-related topic. The results were discussed in relation to their implications for integrating workers with mental retardation into settings with nonhandicapped workers.

Maladaptive behaviors associated with neuroleptic drug maintenance.

In this study we examined whether the decision to maintain mentally retarded persons on neuroleptic drugs was associated with specific maladaptive behaviors. A drug-withdrawal group, a drug-reinstatement group, and a drug-control group were used. A two-way repeated measures multivariate analysis of variance design indicated that mentally retarded persons were more likely to be maintained on drugs because of events that were perceived as significant and recorded by institutional staff in clinical notes than because of the reasons for which the drugs were prescribed initially. In particular, staff members' perceptions of disturbing behavior, self-stimulation, and physical aggression were likely to influence their decision to maintain mentally retarded persons on neuroleptics.

Social ecology of the workplace: employers' perceptions versus direct observation.

In this study, the social interactions of nonhandicapped employees in seven different competitive employment sites were observed directly using narrative recording procedures. The data were analyzed to determine if there was a correspondence between employers' expectations for social behaviors and those social behaviors directly observed. The results are discussed in relationship to the curriculum implications they have for transitioning youths and adults with handicaps into similar employment settings.

Pyrimethamine-sulfadoxine still effective against Plasmodium falciparum in Jayapura, Irian Jaya: RI-type resistance in 2 of 18 patients.

The sensitivity of Plasmodium falciparum infections to pyrimethamine-sulfadoxine was studied in 18 Indonesian patients in Jayapura, Irian Jaya. In 16 of the 18 patients parasitaemia was cleared by day 6 and the patients remained without parasitaemia through day 28. Two of the 18 patients had late recrudescences consistent with RI-type resistance; one each on days 14 and 21. Pyrimethamine-sulfadoxine is still an effective antimalarial for most patients with falciparum malaria in Jayapura.