Evaluation of melanin-targeted radiotherapy in combination with radiosensitizing drugs for the treatment of melanoma

The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. An [131I]-labeled benzamide - [131I]MIP-1145 - selectively targets melanin, reduces melanoma tumor burden and increases survival in preclinical models. Our purpose was to determine the potential of radiosensitizers to enhance the anti-tumor efficacy of [131I]MIP-1145. Melanotic (A2058) and amelanotic (A375 and SK-N-BE(2c)) cells were treated with [131I]MIP-1145 as a single agent or in combination with drugs with radiosenitizing potential. Cellular uptake of [131I]MIP-1145 and toxicity were assessed in monolayer culture. The interaction between radiosensitizers and [131I]MIP-1145 was evaluated by combination index analysis in monolayer cultures and by delayed growth of multicellular tumor spheroids. [131I]MIP-1145 was taken up by and was toxic to melanotic cells but not amelanotic cells. Combination treatments comprising [131I]MIP-1145 with the topoisomerase inhibitor topotecan or the PARP-1 inhibitor AG014699 resulted in synergistic clonogenic cell kill and enhanced delay of the growth of spheroids derived from melanotic melanoma cells. The proteasome inhibitor bortezomib had no synergistic cytotoxic effect with [131I]MIP-1145 and failed to enhance the delay of spheroid growth. Following combination treatment of amelanotic cells, neither synergistic clonogenic cell kill nor enhanced growth delay of spheroids was observed

Helping you helps me: giving and receiving social support in recovery groups for problem gamblers

Mutual aid fellowships are the most accessible and widely used treatments for different addictive behaviors including problem gambling, yet how and why such treatments may be effective remains underexplored. The present research investigated the relationships between recovery group identification, social support received and provided to the recovery group, and important recovery-related outcomes among people attending Gamblers Anonymous (GA). Recovery group identification was associated with increased abstinence self-efficacy and decreased perceived risk in gambling-related ‘trigger’ situations and these relationships were mediated by the perceived provision of social support but not its receipt. The findings suggest that mutual aid fellowships such as GA may be effective in part because they provide opportunities for members to not only receive social support from similar others but also to make a meaningful contribution to other people’s recovery through the provision of social support, which can aid their own recovery

Investigation of the role of T cells in airway inflammation using novel murine models of disease

Asthma is a highly prevalent disease characterised by variable airflow obstruction, bronchial hyperresponsiveness and airways inflammation. Studies over the last 20 years have established that an immunological response centred on Th2 lymphocytes and their mediators is critical to the development of the disease, although other elements including structural cells are thought to contribute to the final outcome. In this thesis animal models have been developed to investigate the role of inflammation in the development and progression of allergic airways disease. As CD4+ T cells have been suggested as a possible therapeutic target in asthma, techniques were employed that allowed the identification and quantification of antigen-specific T cells in different anatomically relevant compartments including, draining and peripheral lymph nodes, lungs and bronchoalveolar lavage fluid, providing novel information on the role of T ceils in these models. This information produced has important implications for future development of therapeutic agents targeting T cells. To investigate the role of antigen-specific T cells in airways inflammation, an adoptive transfer model was established. The aim of the model was to allow tracking of antigen-specific T cells as well as inducing airway eosinophilia in conjunction with IgE production and associated Th2 cytokines. Our investigations revealed that a single immunisation with OVA followed by 1-3 intranasal antigen airway challenges did not induce BAL eosinophilia although identification of Ag-specific T cells was possible in the lymph nodes and the lung. However, it was found that a more aggressive regime of three immunisations and one airways challenge was required to induce lung eosinophilia and associated pathology (long model). Manipulation of the single immunisation, single airway challenge with the addition of LPS to antigen in the airways challenge resulted in lung eosinophilia and pathology (short model) as seen in the three prime, one challenge model, demonstrating that different models can be adapted to produce the same outcome. It was found that when antigen-specific T cells were compared between the two models where pathology or no pathology was see, resulted in different expression of certain cytokines, costimulatory molecules and chemokine receptors. When no pathology was present, it was found that IFNy was upregulated in both models. In the long model when pathology was present, IL-5 expression was upregulated, and in contrast IL-13 was upregulated in the short model when pathology was induced, with CCR3 upregulated in both models. This data demonstrates that although similar endpoints were observed the route by which the response was initiated differs. To determine the site of T cell division in airway inflammation, antigen-specific T cells were tracked in different compartments throughout the course of disease and their expression of proliferating cell nuclear antigen (PCNA) was measured as an indication of their recent division. When T cell division was quantified by LSC in the long model it was found that there was an early wave of T cell division seen in the lung, followed by similar in the draining lymph node. Subsequently, another wave of antigen-specific T cell division was seen in the lung tissue. The early T cell division may have been caused by uptake and presentation of antigen by resident dendritic cells, which have been shown to be present in the lung. The location of these dendritic cells allows them to have direct contact with incoming antigens. It is known that there is a dendritic cell network situated immediately above and beneath the basement membrane of the upper and lower airways enabling these cells to sample the epithelium for inhaled antigens. It has also been shown in experimental models of respiratory infection that a population of memory T cells are established in the lung parenchyma and the lung airways. Airway resident memory cells contribute significantly to recall responses by providing immediate effector activity at the site of antigen entry, showing that there is local antigen presentation in the lung. This data gives an insight into the location and timing of T cell division and activation and may enable more accurate therapeutic intervention in airways inflammation. (Abstract shortened by ProQuest.)

Household Equipment for Lefthanders: Ambidextrous Design

This study came about as the result of many years of observing the world "through the looking-glass." It is hoped that this study will spark new ideas for the betterment of design. It is also hoped that this study will be a comfort and encouragement to lefthandersHousing and Interior Desig

Seven Years of Permanent Running of MELFI-1 on Board the ISS and Utilisation of the Three MELFI Units Refrigeration Pool

The pool of three Minus Eighty Laboratory freezer for ISS (MELFI) units continues providing the scientific community with robust and permanent freezer and refrigeration capabilities for life science experiments on the International Space Station (ISS). Launched in 2006, the first unit will complete, by summer 2013, seven years of continuous operations without intervention on the internal Nitrogen gas cycle, while all necessary hardware and operations were initially planned for preventive maintenance every two years. This unit has demonstrated outstanding performance on orbit and proved the technical decisions made during the development program. Current utilization of MELFI units in the ISS is taking full benefit of the initial specifications, which allows for wide adaptations to cope with the mission scenario imposed by the life extension in orbit. The two other MELFI units, launched respectively in 2008 and 2009, are supporting the first unit providing additional conditioned volume necessary for the science on board, and also for preparing thermal mass used to protect the samples on their way down to earth. The MELFI pool is outfitted with all supporting hardware to allow for extended operation on orbit including preventive and corrective maintenance. The internal components were designed to allow for easy on board maintenance. Spare equipment was installed in the MELFI rack on ISS and specific maintenance means were developed which required crew training before the cold gas cycle could be accessed. The paper will present first how the design choices made for the initial missions are identifying features necessary for extended duration missions, and will then give highlights on the utilization of the MELFI refrigeration pool during the recent years in ISS

Antigen depot is not required for alum adjuvanticity

Alum adjuvants have been in continuous clinical use for more than 80 yr. While the prevailing theory has been that depot formation and the associated slow release of antigen and/or inflammation are responsible for alum enhancement of antigen presentation and subsequent T- and B-cell responses, this has never been formally proven. To examine antigen persistence, we used the chimeric fluorescent protein EαGFP, which allows assessment of antigen presentation in situ, using the Y-Ae antibody. We demonstrate that alum and/or CpG adjuvants induced similar uptake of antigen, and in all cases, GFP signal did not persist beyond 24 h in draining lymph node antigen-presenting cells. Antigen presentation was first detectable on B cells within 6–12 h of antigen administration, followed by conventional dendritic cells (DCs) at 12–24 h, then finally plasmacytoid DCs at 48 h or later. Again, alum and/or CpG adjuvants did not have an effect on the magnitude or sequence of this response; furthermore, they induced similar antigen-specific T-cell activation in vivo. Notably, removal of the injection site and associated alum depot, as early as 2 h after administration, had no appreciable effect on antigen-specific T- and B-cell responses. This study clearly rules out a role for depot formation in alum adjuvant activity

Strongly lensed [O III] emitters at Cosmic Noon with Roman: Characterizing extreme emission line galaxies on star cluster complex scales (100 pc)

Extreme emission line galaxies (EELGs) are considered the primary contributor to cosmic reionization and are valuable laboratories to study the astrophysics of massive stars. It is strongly expected that Roman's High Latitude Wide Area Survey (HLWAS) will find many strongly gravitationally lensed [O III] emitters at Cosmic Noon (1 < z < 2.8). Roman imaging and grism spectroscopy alone will simultaneously confirm these strong lens systems and probe their interstellar medium (ISM) and stellar properties on small scales ($\lesssim$ 100 pc). Moreover, these observations will synergize with ground-based and space-based follow-up observations of the discovered lensed [O III] emitters in multi-wavelength analyses of their properties (e.g., massive stars and possible escape of ionizing radiation), spatially resolved on the scales of individual star cluster complexes. Only Roman can uniquely sample a large number of lensed [O III] emitters to study the small scale (~ 100 pc) ISM and stellar properties of these extreme emission line galaxies, detailing the key physics of massive stars and the ISM that govern cosmic reionization.Comment: Submitted in response to the call for Roman Telescope CCS white paper

Performance feedback: An exploratory study to examine the acceptability and impact for interdisciplinary primary care teams

Background - This mixed methods study was designed to explore the acceptability and impact of feedback of team performance data to primary care interdisciplinary teams. // Methods - Seven interdisciplinary teams were offered a one-hour, facilitated performance feedback session presenting data from a comprehensive, previously-conducted evaluation, selecting highlights such as performance on chronic disease management, access, patient satisfaction and team function. // Results - Several recurrent themes emerged from participants' surveys and two rounds of interviews within three months of the feedback session. Team performance measurement and feedback was welcomed across teams and disciplines. This feedback could build the team, the culture, and the capacity for quality improvement. However, existing performance indicators do not equally reflect the role of different disciplines within an interdisciplinary team. Finally, the effect of team performance feedback on intentions to improve performance was hindered by a poor understanding of how the team could use the data. // Conclusions - The findings further our understanding of how performance feedback may engage interdisciplinary team members in improving the quality of primary care and the unique challenges specific to these settings. There is a need to develop a shared sense of responsibility and agenda for quality improvement. Therefore, more efforts to develop flexible and interactive performance-reporting structures (that better reflect contributions from all team members) in which teams could specify the information and audience may assist in promoting quality improvement

High-Redshift Galaxy Candidates at z=9−13z = 9-13 as Revealed by JWST Observations of WHL0137-08

JWST was designed to peer into the distant universe and study galaxies nearer the beginning of time than previously. Here we report the discovery of 12 galaxy candidates observed 300-600 Myr after the Big Bang with photometric redshifts between z ~ 8.5-13 measured using JWST NIRCam imaging of the galaxy cluster WHL0137 observed in 8 filters spanning 0.8-5.0 $\mu$m, plus 9 HST filters spanning 0.4-1.7 $\mu$m. Three of these candidates are gravitationally lensed by the foreground galaxy cluster and have magnifications of $\mu \sim 3 - 8$. The remaining nine candidates are located in a second JWST NIRCam module, centered ~29' from the cluster center, with expected magnifications of $\mu$ <~ 1.1. Our sample of high-redshift candidates have observed F200W AB magnitudes between 25.9 and 28.1 mag and intrinsic F200W AB magnitudes between 26.4 and 29.7 mag ($M_{UV}$ = -22.5 to -17). We find the stellar masses of these galaxies are in the range $\log M_{*}/M_{\odot}$ = 8 - 9, and down to 7.5 for the lensed galaxies. All are young with mass-weighted ages < 100 Myr, low dust content $A_V$ < 0.15 mag, and high specific star formation rates sSFR ~10-50 Gyr$^{-1}$ for most. One z ~ 9 candidate is consistent with an age < 5 Myr and a sSFR ~250 Gyr$^{-1}$, as inferred from a strong F444W excess, implying [OIII]+H-beta rest-frame equivalent width ~2000 Angstrom, although an older and redder z~ 10 object is also allowed. Another z~9 candidate ID9356 is lensed into an arc 2.6" long by the effects of strong gravitational lensing ($\mu$~8), and has at least two bright knots of unevenly distributed star formation. This arc is the most spatially-resolved galaxy at z~9 known to date, revealing structures ~30 pc across. Follow-up spectroscopy of WHL0137 with JWST/NIRSpec is planned for later this year, which will validate some of these candidates and study their physical properties in more detail.Comment: submitted to Ap