[Stereotactic radiotherapy for operable stage I non-small cell lung cancer]. / Place de la radiothérapie stéréotaxique pour les cancers bronchiques non à petites cellules de stade I opérables.

Standard treatment stage of non-small cell lung cancer is currently surgery. For inoperable patients, stereotactic body radiotherapy is the reference treatment. This non-invasive technique has developed considerably and its excellent results in terms of carcinological control and tolerance raise the question of its indication for operable patients, especially for old patients and/or with comorbidities. This article reviews the available data in the literature of the place of stereotactic body radiotherapy for medically operable patients with stage I non-small cell lung cancer.

No effect of ambient odor on the affective appraisal of a desktop virtual environment with signs of disorder.

BACKGROUND: Desktop virtual environments (VEs) are increasingly deployed to study the effects of environmental qualities and interventions on human behavior and safety related concerns in built environments. For these applications it is essential that users appraise the affective qualities of the VE similar to those of its real world counterpart. Previous studies have shown that factors like simulated lighting, sound and dynamic elements all contribute to the affective appraisal of a desktop VE. Since ambient odor is known to affect the affective appraisal of real environments, and has been shown to increase the sense of presence in immersive VEs, it may also be an effective tool to tune the affective appraisal of desktop VEs. This study investigated if exposure to ambient odor can modulate the affective appraisal of a desktop VE with signs of public disorder. METHOD: Participants explored a desktop VE representing a suburban neighborhood with signs of public disorder (neglect, vandalism and crime), while being exposed to either room air or subliminal levels of unpleasant (tar) or pleasant (cut grass) ambient odor. Whenever they encountered signs of disorder they reported their safety related concerns and associated affective feelings. RESULTS: Signs of crime in the desktop VE were associated with negative affective feelings and concerns for personal safety and personal property. However, there was no significant difference between reported safety related concerns and affective connotations in the control (no-odor) and in each of the two ambient odor conditions. CONCLUSION: Ambient odor did not affect safety related concerns and affective connotations associated with signs of disorder in the desktop VE. Thus, semantic congruency between ambient odor and a desktop VE may not be sufficient to influence its affective appraisal, and a more realistic simulation in which simulated objects appear to emit scents may be required to achieve this goal.

Does training general practitioners to elicit patients' illness representations and action plans influence their communication as a whole?

OBJECTIVE: To examine whether the discussion of illness representations and action plans during medical encounters affects the way patients and general practitioners (GPs) communicate. METHODS: In a quasi-experimental design, 10 GPs first performed care-as-usual conversations with patients. After a 6 h training they performed consultations either emphasizing patients' illness representations or action plans. Data were collected from 70 videotaped consultations with hypertensive patients, which were analyzed using the Roter Interaction Analysis System. RESULTS: Compared with care-as-usual consultations, communication in the action plan condition resulted in an increased discussion of lifestyle issues whereas communication in the illness representation condition resulted in more discussion of patient concerns. In both experimental conditions the proportion of affective GP utterances was higher while patients contributed more to the conversation. When GPs changed their communication style, patients did accordingly. CONCLUSION: The explicit address of illness representations or action plans during consultations results in more attention to patient concerns and lifestyle issues and an overall improvement in patient-GP communication in terms of affective atmosphere and patient involvement. PRACTICE IMPLICATIONS: These findings show that after a brief training GPs are able to change their communication style in a way that allows for a more thorough consideration of patient self-management.

Quality of life in adolescents born small for gestational age: does growth hormone make a difference?

BACKGROUND/AIMS: To evaluate quality of life (QoL) in adolescents born SGA without spontaneous catch-up growth, treated with and without long-term growth hormone (GH) therapy. Additionally, to assess whether GH treatment has a positive effect on QoL, besides improving adult height and height SDS during childhood. METHODS: Two groups of adolescents born SGA without spontaneous catch-up growth participated in the QoL evaluation; a GH-treated group (n = 44, mean GH duration: 8.8 (1.7) years) and an untreated group (n = 28), both mean age 15.8 (2.1) years. QoL was measured by self-reports of the TACQOL-S, a disorder-specific questionnaire, and the CHQ, a generic questionnaire. RESULTS: The GH group scored significantly better health status and health-related QoL on several scales of the TACQOL-S. On all TACQOL-S scales the GH group scored better QoL than the untreated group, with effect sizes of moderate to large, not all differences reaching statistical significance. The generic CHQ did not reveal significant differences in QoL between the GH group and the untreated group. CONCLUSIONS: Firstly, adolescents born SGA, with a GH-induced improved height, had in many aspects a better QoL than untreated adolescents born SGA, according to the disorder-specific questionnaire. Secondly, we advise to use, in addition to a generic questionnaire, a disorder-specific questionnaire for measuring QoL in children treated for short stature, as the generic CHQ did not reveal such differences.

Models and theories in studies on educating and counseling children about physical health: a systematic review.

The aim of this review is to gain a comprehensive view on the theories and models referred to in studies on educating and counseling children about physical health. A computer search was conducted using PubMed Medline, and Silverplatter Webspirs Psycinfo. Original studies, reviews, and theoretical papers published between 1992-2003 were included. The review presents the results of the 35 studies in which the majority of the subjects were between 0 and 12 years of age. A classification system is proposed that helped grouping the models, and the interrelationship between this classification and the characteristics of the reviewed studies is explored. The classification could function as an introductory guide and help to select appropriate theories and models when defining future research agenda's. The results of this review may attribute to the refinement of the theoretical underpinning of child education and counseling in physical health.

Manipulation of patient-provider interaction: discussing illness representations or action plans concerning adherence.

According to Leventhal's Self-Regulatory Model of Illness, patients have ideas and action plans related to the management of their disease. The aim of this study is to examine whether ideas and action plans relating to hypertension change as a result of general practitioner's (GP's) discussing them during consultation, and whether these changed ideas and actions plans affect adherence. The study employed an experimental design, highlighting three conditions: (0) care-as-usual consultation; (1) discussing patient's ideas about their disorder; and (2) discussing patient's action plans. Ten GP-trainees performed care-as-usual consultations, were subsequently assigned to a training in either Condition 1 or 2, and performed the trained conversations. Hundred and eight patients with hypertension were consecutively assigned to the conditions, and completed questionnaires a week before, immediately after the consultation, and 1 month later. The training resulted in two new, feasible and different types of conversations that managed to affect some of the patient's ideas and action plans. It is concluded that the study provided GPs with a tool to discuss illness representations and actions plan of patients with hypertension. Implications for the management of hypertension adherence in primary care are discussed.

Quality of life and self-esteem in children treated for idiopathic short stature.

OBJECTIVE: Changes in health-related quality of life (HRQOL) and self-esteem were studied in children with idiopathic short stature (ISS) participating in a study on the effect of growth hormone treatment. STUDY DESIGN: Prepubertal children (n = 36) with ISS were randomly assigned to a treatment or control group. Children with ISS, their parents, and the pediatrician completed HRQOL and self-esteem questionnaires 3 times in 2 years. RESULTS: At the start, children with ISS did not have lower scores than the norm population, except for social functioning HRQOL. The pediatrician reported an improvement of HRQOL in the treatment group, the parents reported no change, and the children in the treatment group reported the same, or sometimes even worse, HRQOL or self-esteem than the control group. Changes related to the child's satisfaction with height and hardly to growth itself. CONCLUSION: The assumption that growth hormone treatment improves HRQOL in children with ISS could not be supported in this study.

Transcription factor activation in lymphokine activated killer cells and lymphocytes from patients receiving IL-2 immunotherapy.

Administration of the cytokine interleukin-2 (IL-2) can result in therapeutic benefits for individuals with renal cell carcinoma and melanoma. Here we report an analysis of the transcription factor families AP-1, Sp1, NF-kappaB, and signal transducers and activators of transcription (STAT) in cancer patients' lymphocytes before and after IL-2 immunotherapy, as assessed by a gel-shift assay. An in vitro surrogate of IL-2 immunotherapy is the incubation of fresh peripheral blood mononuclear cells (PBMC) from healthy individuals in IL-2 for several days, resulting in the production of lymphokine-activated killer (LAK) activity in these cultures. One purpose of this study was to describe the profile of transcription factor activation in these different populations, and assess whether the patterns observed correlated with functional differences in these cells. Prior to in vivo IL-2 administration, the typical binding pattern of transcription factors in PBMC from patients resembled that seen in fresh PBMC from healthy individuals. Over a 3-week course of IL-2 therapy, in most patients the binding patterns of AP-1 , Sp1, and NF-kappaB proteins changed to resemble those seen in PBMC activated by IL-2 in vitro. However, the cells obtained from IL-2-treated patients did not have low-level constitutive expression of STAT binding factors as did LAK cells. When these patient cells were further stimulated by IL-2 in vitro, additional differences in STAT induction patterns were noted. These data provide further information on the molecular events occurring in immune cells generated through in vivo and in vitro administration of IL-2, and further document that there is not a precise congruence between PBMC activated in vivo and in vitro by IL-2.

TAG-72-reactive antibody CC49 recognizes molecules expressed by hematopoietic cell lines.

Aberrant glycosylation of mucins on the surface of adenocarcinomas leads to exposure of novel tumor-associated epitopes potentially recognizable by the immune system. Monoclonal antibodies (mAbs) have been developed against some of these epitopes. One such mAb, denoted CC49, recognizes the tumor-associated glycoprotein TAG-72. Most adenocarcinomas, including breast, colon, ovarian, prostate, and gastric, express some form of this molecule, recognizable by the CC49 antibody. The widespread distribution of the antigen on transformed cells makes the CC49 mAb a potentially powerful tool in numerous immunotherapy contexts. In the course of our studies with CC49 and certain of its molecularly engineered derivatives, we screened a number of human hematopoietic cell lines for TAG-72 expression by flow cytometry using CC49. We found that the T-cell line, Jurkat, had a higher level of CC49 mAb binding than any of the carcinoma cell lines previously evaluated in our laboratory. In addition, the myelomonocytic cell line Tf-1 and the erythroleukemia cell line K562 were also positive for CC49 mAb binding by flow-cytometric analysis. However, peripheral blood lymphocytes and certain other hematopoietic cell lines were not able to bind the CC49 mAb. Immunoblot analyses of cell extracts from the CC49 reactive lines indicated distinct protein species reactive with the CC49 antibody. In some instances, cells expressing these reactive proteins were susceptible to antibody-dependent cellular cytotoxicity using a chimeric derivative of the CC49 antibody. These results indicate that the cell membrane expression of molecules recognized by CC49 extends beyond adenocarcinomas to certain cell lines of hematopoietic origin.

Differential utilization of IFN-gamma-responsive elements in two maturationally distinct macrophage cell lines.

We have characterized the transcriptional response to IFN-gamma in two maturationally distinct macrophage populations: the mature RAW 264.7 cell line, phenotypically identical to thioglycollate-elicited peritoneal macrophages, and the less mature WEHI-3 cell line. We first investigated the use of two IFN-gamma-responsive regulatory elements, the interferon-stimulated response element (ISRE) and the gamma-activated sequence (GAS), in these cells. Transient transfection assays revealed that synthetic promoter constructs containing either the ISRE or GAS regulatory motif fused to a luciferase reporter gene were transcriptionally inactive in the WEHI-3 cell line. We then analyzed the expression in the two cell lines of a panel of known IFN-gamma-responsive genes that are transcriptionally controlled by different regulatory elements. RT-PCR analysis revealed that both cell lines responded to IFN-gamma treatment by up-regulating genes that are transcriptionally controlled by kappa B or W box DNA binding motifs. However, genes regulated by ISRE or GAS elements were induced by IFN-gamma only in the RAW 264.7 cell line. Kinetic analysis of the transcriptional activity of synthetic promoter constructs in the RAW 264.7 cell line showed rapid IFN-gamma induction through both the ISRE and GAS motifs, indicating that both elements are utilized early after IFN-gamma stimulation in mature macrophages. These results suggest that cis-acting DNA response element utilization, and the subsequent profiles of IFN-gamma-induced gene expression, differ in macrophages at different stages of maturation.

Expression of a tumor-reactive antibody-interleukin 2 fusion protein after in vivo particle-mediated gene delivery.

We have used a particle-mediated gene transfer method to analyze the posttransfection expression pattern of an antibody-cytokine fusion protein (FP) in vivo. The FP, denoted CC49-IL2, consists of a single-chain antibody containing the antigen recognition domain from the murine monoclonal antibody CC49 (recognizing the tumor-associated antigen TAG-72), a human IgG1 constant heavy chain, and human interleukin-2 (IL-2). This FP can bind to TAG-72-expressing tumor cells and exhibits IL-2 activity. To induce systemic levels of this FP in vivo, we have transferred the FP gene into murine epidermal cells by direct delivery of DNA-coated gold particles using a transcutaneous "gene gun." After the pericutaneous delivery of the FP gene via gold particles, production of the exogenous FP was detected at the epidermal target site. The FP produced in vivo at the site of gene delivery has cytokine activity and antigen recognition capabilities similar to those present in CC49-IL2 FP purified from hybridoma culture supernatants in vitro. FP was also detectable in the serum from test animals treated with particle-mediated gene transfer. Time course experiments indicated that serum levels of FP reached a peak level within 8 hours after DNA delivery, whereas the epidermal target tissue levels continued to increase for 24 hours before plateauing. Our results indicate that exogenous protein levels consistent with immunotherapeutic effects of the FP can be readily achieved at the skin tissue site of gene delivery, with the potential for achieving therapeutic levels systemically.

Promoter analysis of an interferon-inducible gene associated with macrophage activation.

We have investigated the regulation of an activation-associated guanylate-binding protein gene (mGBP-1/mag-1) in murine macrophage cell lines in response to the cytokine IFN-gamma. One of the cell lines utilized (RAW 264.7) acquires the ability to kill tumor cells after IFN-gamma and LPS treatment, whereas the other (WEHI-3) does not. We previously have demonstrated that mGBP-1 is induced by IFN-gamma in RAW 264.7 but not WEHI-3 cells. Here we present information concerning the cloning, sequencing, and initial characterization of the upstream region of the mGBP-1 gene as a first step towards understanding the differential control of this gene in RAW 264.7 versus WEHI-3 cells. Genomic fragments encompassing a portion of the mGBP-1 5' flanking region were inserted into vectors containing a luciferase reporter gene. 928 bp of upstream sequence were found to be sufficient for IFN-gamma-mediated induction of luciferase activity in the RAW 264.7 cell line. Furthermore, sequences within 100 bp of the major transcription initiation site conferred strong IFN-gamma responsiveness to the reporter gene. A perfect match to the interferon-stimulated response element (ISRE) was present within this region, and was shown to be essential for interferon-induced expression. An oligonucleotide corresponding to the mGBP-1 ISRE bestowed interferon-inducible expression on a heterologous minimal promoter. Site-specific mutation of the ISRE within the 106-bp upstream region eliminated interferon inducibility of this construct. Taken together, the results indicate the ISRE is necessary and sufficient for IFN-gamma induction of the mGBP-1 gene. Transient transfection assays carried out with the WEHI-3 cell line indicated that all promoter constructs were transcriptionally inactive in these cells, including the ISRE-minimal promoter construct. The inability of the WEHI-3 cell line to utilize an ISRE after IFN-gamma induction may underlie the functional differences exhibited by the two cell lines after IFN-gamma stimulation.

The translation machinery and 70 kd heat shock protein cooperate in protein synthesis.

The function of the yeast SSB 70 kd heatshock proteins (hsp70s) was investigated by a variety of approaches. The SSB hsp70s (Ssb1/2p) are associated with translating ribosomes. This association is disrupted by puromycin, suggesting that Ssb1/2p may bind directly to the nascent polypeptide. Mutant ssb1 ssb2 strains grow slowly, contain a low number of translating ribosomes, and are hypersensitive to several inhibitors of protein synthesis. The slow growth phenotype of ssb1 ssb2 mutants is suppressed by increased copy number of a gene encoding a novel translation elongation factor 1 alpha (EF-1 alpha)-like protein. We suggest that cytosolic hsp70 aids in the passage of the nascent polypeptide chain through the ribosome in a manner analogous to the role played by organelle-localized hsp70 in the transport of proteins across membranes.

Identification and characterization of a new gene family induced during macrophage activation.

In this report, we describe the primary structure and regulation of two novel IFN-gamma-inducible genes expressed during the process of macrophage activation. We used the RAW 264.7 cell line to prepare a cDNA library, from which inducible genes were selected by differential hybridization. Two cDNA clones, mag-1 and mag-2 (for macrophage-activation gene-1 and -2), were induced by IFN-gamma treatment in both RAW 264.7 cells and thioglycolate-elicited peritoneal macrophages, but not in the noncytolytic cell line, WEHI-3. A comparison of the nucleotide and deduced amino acid sequences of clones mag-1 and mag-2 with sequences in available data bases revealed no homologs. However, comparison of mag-1 and mag-2 sequences with each other revealed that these genes are homologous, with conserved residues concentrated at the amino terminus. Kinetic analyses revealed similar temporal patterns of induction of mRNA expression for these genes after IFN-gamma treatment. In addition, the genes showed distinct response patterns to the macrophage-activating stimuli IFN-gamma and LPS used either alone or in combination. Analysis of a panel of cell types of various lineages demonstrated that expression of these genes was associated with cellular activation in multiple cell types. As a result of the sequence similarities between these genes, we propose that they define a new family of IFN-gamma-regulated genes in macrophages.

Functional analysis of a conserved amino-terminal region of HSP70 by site-directed mutagenesis.

Hsp70 proteins have been highly conserved throughout evolution. As a first step in a structure-function analysis of hsp70, we constructed and analysed the consequences of mutations in a portion of the SSA1 gene, a member of the Saccharomyces cerevisiae HSP70 multigene family, that encodes a nearly invariant region near the amino terminus. Analysis of strains expressing SSA1 proteins with alterations at positions 8, 11 and 15 showed that these conserved residues within this region are critical for normal functioning of the protein. SSA1 protein containing either of two changes at position 15 was able to slightly complement the inviability of an ssa1ssa2ssa4 strain, but was inactive in other complementation assays. The other mutant proteins tested were unable to complement any tested phenotype. Effective interallelic complementation of several phenotypes was observed when a mutant protein substituted at position 8 was expressed in the same cell with either of two proteins carrying substitutions at position 15, suggesting that hsp70 acts as a multimer. Evidence from previous studies suggests that hsp70 proteins engage in ATP-driven cycles of binding and release from peptides. The ability of the mutant proteins to bind ATP and a peptide was tested. The Ssa1p carrying a substitution at position 8, which inhibits growth of cells carrying wild-type SSA proteins, showed a defect in release from a peptide relative to wild type. Two mutations, one each at position 8 and 15, resulted in accumulation of phosphorylated isoforms which may be a normal, transient hsp70 intermediate.

Characterization of the RAD10 gene of Saccharomyces cerevisiae and purification of Rad10 protein.

The RAD10 gene of Saccharomyces cerevisiae is one of at least five genes required for damage-specific incision of DNA during nucleotide excision repair. This gene was previously cloned and sequenced [Weiss, W. A., & Friedberg, E. C. (1985) EMBO J. 4, 1575-1582; Reynolds et al. (1985) EMBO J. 4, 3549-3552]. In the present studies, we have mapped one major and three minor transcriptional start sites in the RAD10 gene. The locations of these sites relative to the translational start codon are remarkably similar to those previously identified in the yeast RAD2 gene [Nicolet et al. (1985) Gene 36, 225-234]. The two genes also share common sequences in these regions. However, in contrast to RAD2 [Robinson et al. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 1842-1846], RAD10 is not induced following exposure of cells to the DNA-damaging agent 4-nitroquinoline 1-oxide. Native RAD10 protein and also two different Rad10 fusion proteins are rapidly degraded in most Escherichia coli strains. However, following overexpression of the cloned RAD10 gene in yeast, native Rad10 protein was purified to greater than 90% homogeneity. A catalytic function has not been identified for the purified protein. RAD10 cells (untransformed with the cloned gene) contain fewer than 500 molecules per cell. This is similar to the levels of the UvrA, UvrB, and UvrC nucleotide excision repair proteins in E. coli.