Effect of low-dose chest irradiation before chemotherapy on the rate of local failure in small-cell lung cancer.

PURPOSE: To evaluate the rate of tumor recurrence within the irradiated volume after initial low-dose irradiation of limited-stage small-cell lung cancer (SCLC), to assess the tolerance of a sequential combination of low-dose chest irradiation followed by chemotherapy, and to confirm the responsiveness of limited-stage SCLC to low-dose irradiation. METHODS AND MATERIALS: In this pilot study, 26 patients with limited-stage SCLC were treated by first-line 20-Gy thoracic irradiation followed 3 weeks later by chemotherapy (cisplatin, doxorubicin, and etoposide for six cycles). RESULTS: We present our final results with a median follow-up of surviving patients of 7 years. The response rate to this low-dose irradiation was 83%, with an overall response rate to radiochemotherapy of 96% and a median survival of 21 months. No unexpected early or late toxicity was observed. The rate of initial isolated local failure was 8%, which compares favorably with other published series using higher doses of radiochemotherapy. CONCLUSION: An initial chest irradiation of 20 Gy before chemotherapy could be sufficient to reduce the risk of local failure during the time of survival of patients with limited-stage SCLC. Potential advantages of this treatment may be the prevention of resistance mechanisms to radiotherapy induced by preliminary chemotherapy and a reduced radiation-induced toxicity.

The role of NFI-C liver regeneration and its potential function as a general regulator of regenerative processes

Collectively, research aimed to understand the regeneration of certain tissues has unveiled the existence of common key regulators. Knockout studies of the murine Nuclear Factor I-C (NFI-C) transcription factor revealed a misregulation of growth factor signaling, in particular that of transforming growth factor ß-1 (TGF-ßl), which led to alterations of skin wound healing and the growth of its appendages, suggesting it may be a general regulator of regenerative processes. We sought to investigate this further by determining whether NFI-C played a role in liver regeneration. Liver regeneration following two-thirds removal of the liver by partial hepatectomy (PH) is a well-established regenerative model whereby changes elicited in hepatocytes following injury lead to a rapid, phased proliferation. However, mechanisms controlling the action of liver proliferative factors such as transforming growth factor-ßl (TGF-ß1) and plasminogen activator inhibitor-1 (PAI-1) remain largely unknown. We show that the absence of NFI-C impaired hepatocyte proliferation due to an overexpression of PAI-1 and the subsequent suppression of urokinase plasminogen (uPA) activity and hepatocyte growth factor (HGF) signaling, a potent hepatocyte mitogen. This indicated that NFI-C first acts to promote hepatocyte proliferation at the onset of liver regeneration in wildtype mice. The subsequent transient down regulation of NFI-C, as can be explained by a self- regulatory feedback loop with TGF-ßl, may limit the number of hepatocytes entering the first wave of cell division and/or prevent late initiations of mitosis. Overall, we conclude that NFI-C acts as a regulator of the phased hepatocyte proliferation during liver regeneration. Taken together with NFI-C's actions in other in vivo models of (re)generation, it is plausible that NFI-C may be a general regulator of regenerative processes. - L'ensemble des recherches visant à comprendre la régénération de certains tissus a permis de mettre en évidence l'existence de régulateurs-clés communs. L'étude des souris, dépourvues du gène codant pour le facteur de transcription NFI-C (Nuclear Factor I-C), a montré des dérèglements dans la signalisation de certains facteurs croissance, en particulier du TGF-ßl (transforming growth factor-ßl), ce qui conduit à des altérations de la cicatrisation de la peau et de la croissance des poils et des dents chez ces souris, suggérant que NFI-C pourrait être un régulateur général du processus de régénération. Nous avons cherché à approfondir cette question en déterminant si NFI-C joue un rôle dans la régénération du foie. La régénération du foie, induite par une hépatectomie partielle correspondant à l'ablation des deux-tiers du foie, constitue un modèle de régénération bien établi dans lequel la lésion induite conduit à la prolifération rapide des hépatocytes de façon synchronisée. Cependant, les mécanismes contrôlant l'action de facteurs de prolifération du foie, comme le facteur de croissance TGF-ßl et l'inhibiteur de l'activateur du plasminogène PAI-1 (plasminogen activator inhibitor-1), restent encore très méconnus. Nous avons pu montrer que l'absence de NFI-C affecte la prolifération des hépatocytes, occasionnée par la surexpression de PAI-1 et par la subséquente suppression de l'activité de la protéine uPA (urokinase plasminogen) et de la signalisation du facteur de croissance des hépatocytes HGF (hepatocyte growth factor), un mitogène puissant des hépatocytes. Cela indique que NFI-C agit en premier lieu pour promouvoir la prolifération des hépatocytes au début de la régénération du foie chez les souris de type sauvage. La subséquente baisse transitoire de NFI-C, pouvant s'expliquer par une boucle rétroactive d'autorégulation avec le facteur TGF-ßl, pourrait limiter le nombre d'hépatocytes qui entrent dans la première vague de division cellulaire et/ou inhiber l'initiation de la mitose tardive. L'ensemble de ces résultats nous a permis de conclure que NFI-C agit comme un régulateur de la prolifération des hépatocytes synchrones au cours de la régénération du foie.

Role of the V-ATPase in regulation of the vacuolar fission-fusion equilibrium.

Like numerous other eukaryotic organelles, the vacuole of the yeast Saccharomyces cerevisiae undergoes coordinated cycles of membrane fission and fusion in the course of the cell cycle and in adaptation to environmental conditions. Organelle fission and fusion processes must be balanced to ensure organelle integrity. Coordination of vacuole fission and fusion depends on the interactions of vacuolar SNARE proteins and the dynamin-like GTPase Vps1p. Here, we identify a novel factor that impinges on the fusion-fission equilibrium: the vacuolar H(+)-ATPase (V-ATPase) performs two distinct roles in vacuole fission and fusion. Fusion requires the physical presence of the membrane sector of the vacuolar H(+)-ATPase sector, but not its pump activity. Vacuole fission, in contrast, depends on proton translocation by the V-ATPase. Eliminating proton pumping by the V-ATPase either pharmacologically or by conditional or constitutive V-ATPase mutations blocked salt-induced vacuole fragmentation in vivo. In living cells, fission defects are epistatic to fusion defects. Therefore, mutants lacking the V-ATPase display large single vacuoles instead of multiple smaller vacuoles, the phenotype that is generally seen in mutants having defects only in vacuolar fusion. Its dual involvement in vacuole fission and fusion suggests the V-ATPase as a potential regulator of vacuolar morphology and membrane dynamics.

The Potential of Friction as a Tool for Winter Maintenance, TR-400, 1998

It is intuitively obvious that snow or ice on a road surface will make that surface more slippery and thus more hazardous. However, quantifying this slipperiness by measuring the friction between the road surface and a vehicle is rather difficult. If such friction readings could be easily made, they might provide a means to control winter maintenance activities more efficiently than at present. This study is a preliminary examination of the possibility of using friction as an operational tool in winter maintenance. In particular, the relationship of friction to traffic volume and speed, and accident rates is examined, and the current lack of knowledge in this area is outlined. The state of the art of friction measuring techniques is reviewed. A series of experiments whereby greater knowledge of how friction deteriorates during a storm and is restored by treatment is proposed. The relationship between plowing forces and the ice-pavement bond strength is discussed. The challenge of integrating all these potential sources of information into a useful final product is presented together with a potential approach. A preliminary cost-benefit analysis of friction measuring devices is performed and suggests that considerable savings might be realized if certain assumptions should hold true. The steps required to bring friction from its current state as a research tool to full deployment as an operational tool are presented and discussed. While much remains to be done in this regard, it is apparent that friction could be an extremely effective operational tool in winter maintenance activities of the future.

Potential-Scour Assessments and Estimates of Maximum Scour at Selected Bridges in Iowa, HR-344, 1995

This report presents the results of potential-scour assessments at 130 bridges and estimates of maximum scour at 10 bridges, in Iowa. All of the bridges evaluated in the study are constructed bridges (not culverts) that are sites of active or discontinued streamflow-gaging stations and peak-stage measurement sites. The period of the study was from October 1991 to September 1994. The potential-scour assessments were made using a potential-scour index developed by the U.S. Geological Survey for a study in Tennessee. Higher values of the index suggest a greater likelihood of scour-related problems occurring at a bridge. The estimates of maximum scour were made using scour equations recommended by the Federal Highway Administration. In this study, the long term aggradation or degradation that occurred during the period of streamflow data collection at each site was evaluated. Although the abutment-scour equation predicted deep scour holes at many of the sites, the only significant abutment scour that was measured was erosion of the embankment at the left abutment at one bridge after a flood.

Potential of kite aerial photography for peatland investigations with examples from Estonia

Tiivistelmä: Leijailmakuvausmenetelmän käyttömahdollisuudet soiden kartoituksessa - esimerkkejä Viron soilta

Field Demonstration and Laboratory Evaluation of Foamed Asphalts - Muscatine County, HR-233, 1985

In view of the energy, environmental, and economic advantages of the foamed asphalt process using local aggregates in cold mixes and the promising results from Research Project HR-212, a 4.2-mile section of county road in Muscatine County was built with foamed asphalt and local aggregates during August-September 1983. Extensive laboratory evaluation was carried out on five plant mixes representing foamed mixes used in the nine test sections, a laboratory prepared foamed mix, and a laboratory prepared hot mix similar to Plant Mix 1. The foamed mixes were compacted, cured under 15 curing conditions and tested for bulk specific gravity, Marshall stability at 77° F and at 140° F, cured moisture content, resilient modulus and effects of moisture damage due to freeze-thaw cycles, water soaking, and vacuum saturation. In addition, four sets of 83 core samples were taken at 1 to 15 months and tested for moisture content, specific gravity, Marshall stability, and resilient modulus. In summary, the test road has performed satisfactorily for almost two years. The few early construction problems encountered were to be expected for experimental projects dealing with new materials and technologies. Overall results to date are encouraging and foamed asphalt mixes have proved to have the potential as a viable base material in areas where marginal aggregates are available. It is hoped and expected that performance evaluation of the test sections will be continued and that more foamed asphalt trial projects will be constructed and monitored so that experiences and findings from this project can be verified and mix design criteria can be gradually established. For future foamed asphalt projects it is recommended that anti-stripping additives, such as hydrated lime, be added in view of the potential moisture susceptibility of foamed mixes observed in the laboratory evaluation.

Potential and limitations of regulatory T-cell therapy in solid organ transplantation.

Over the past few years, the therapeutic potential of Treg has been highlighted in the field of autoimmune diseases and after allogeneic transplantation. The first hurdle for the therapeutic use of Treg is their insufficient numbers in non-manipulated individuals, in particular when facing strong immune activation and expanding effector cells, such as in response to an allograft. Here we review current approaches being explored for Treg expansion in the perspective of clinical therapeutic protocols. We describe different Treg subsets that could be suitable for clinical application, as well as discuss factors such as the required dose of Treg, their antigen-specificity and in vivo stability, that have to be considered for optimal Treg-based immunotherapy in transplantation. Since Treg may not be sufficient as stand-alone therapy for solid organ transplantation in humans, we draw attention to possible hurdles and combination therapy with immunomodulatory drugs that could possibly improve the in vivo efficacy of Treg.

Sex-chromosome turnovers: the hot-potato model.

Abstract Sex-determining systems often undergo high rates of turnover but for reasons that remain largely obscure. Two recent evolutionary models assign key roles, respectively, to sex-antagonistic (SA) mutations occurring on autosomes and to deleterious mutations accumulating on sex chromosomes. These two models capture essential but distinct key features of sex-chromosome evolution; accordingly, they make different predictions and present distinct limitations. Here we show that a combination of features from the two models has the potential to generate endless cycles of sex-chromosome transitions: SA alleles accruing on a chromosome after it has been co-opted for sex induce an arrest of recombination; the ensuing accumulation of deleterious mutations will soon make a new transition ineluctable. The dynamics generated by these interactions share several important features with empirical data, namely, (i) that patterns of heterogamety tend to be conserved during transitions and (ii) that autosomes are not recruited randomly, with some chromosome pairs more likely than others to be co-opted for sex.

Construction and Maintenance Practices to Minimize the Potential Liability of Counties for Roads in Rural Subdivisions, HR-221, 1981

In an earlier research project, HR-204, the magnitude and nature of highway related tort claims against counties in Iowa were investigated. However, virtually all of the claims identified in that research resulted from incidents that occurred in areas with predominantly agricultural land use. With recent increases in the rural non-farm population, many traditionally urban problems are also appearing in built-up areas under county jurisdiction. This trend is expected to continue so that counties must anticipate a change in the nature of the tort claims they will encounter. Problems that heretofore have been unique to cities may become commonplace in areas for which counties are responsible. The research reported here has been directed toward an investigation of those problems in rural subdivisions that lead to claims growing out of the provision of highway services by counties. Lacking a sufficient database among counties for the types of tort claims of interest in this research, a survey was sent to 259 cities in Iowa in order to identify highway related problems leading to those claims. The survey covered claims during a five year period from 1975 to 1980. Over one-third of the claims reported were based on alleged street defects. Another 34 percent of the claims contained allegations of damages due to backup of sanitary sewers or defects in sidewalks. By expanding the sample from the 164 cities that responded to the survey, it was estimated that a total of $49,000,000 in claims had been submitted to all 259 cities. Over 34% of this amount resulted from alleged defects in the use of traffic signs, signals, and markings. Another 42% arose from claims of defects in streets and sidewalks. Payments in settlement of claims were about 13.4% of the amount asked for those claims closed during the period covered by the survey. About $9,000,000 in claims was pending on June 30, 1980 according to the information furnished. Officials from 23 cities were interviewed to provide information on measures to overcome the problems leading to tort claims. On the basis of this information, actions have been proposed that can be undertaken by counties to reduce the potential for highway-related claims resulting from their responsibilities in rural subdivisions and unincorporated communities. Suggested actions include the eight recommendations contained in the final report for the previous research under HR-204. In addition, six recommendations resulted from this research, as follows: 1. Counties should adopt county subdivision ordinances. 2. A reasonable policy concerning sidewalks should be adopted. 3. Counties should establish and implement a system for setting road maintenance priorities. 4. Counties should establish and implement a procedure for controlling construction or maintenance activities within the highway right of way. 5. Counties should establish and implement a system to record complaints that are received relating to highway maintenance and to assure timely correction of defective conditions leading to such complaints. 6. Counties should establish and implement a procedure to ensure timely advice of highway defects for which notice is not otherwise received.