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This study examines math and English standardized test score progress of students who participated in the 21st century program across 2 years of involvement with a focus on the learning trajectories of limited English proficiency (LEP) students. We find that math and English scores are highly associated with the school and program type—even within a single school district. LEP participants are the furthest behind but have the highest gains compared to other participants. Results vary based on the type of outcome (math or reading), the type of activity (academic or enrichment), and the grade level (elementary or middle school).

Purpose – The purpose of this paper is to report on the findings of the first stage of a project seeking to improve interprofessional working between general practice and adult social care teams. It develops the current evidence base through findings from focus groups and reflects on the implications of the findings for interprofessional collaboration. Design/methodology/approach – The project involved running seven focus groups with general practice staff and adult social work teams to explore their perceptions and understanding of each other. Findings – The focus groups highlighted that the negative aspects of interprofessional working outweighed the positives. Negatives included perceptions of different value bases, a lack of knowledge about each others’ roles and responsibilities which resulted in resorting to stereotypes, poor interprofessional communication and a sense of an unspoken professional hierarchy with general practitioners (GPs) at the top leading preventing a culture of appropriate challenge. Research limitations/implications – The research has only been conducted with four GP practices and three social work teams that had expressed an interest in improving their interprofessional working. Therefore the findings may not be generalisable. Practical implications – The case study suggests that there is a lack of effective interprofessional working between social care teams and general practice. With the current health and social care agenda focused on integration, this suggests there should be a greater focus on this area. Originality/value – This paper illustrates that despite many years of policy makers promoting better integration, the quality of the interprofessional collaboration between social care teams and general practice remains poor.

Progress in chronic lymphocytic leukemia (CLL) therapies has extended greatly the length and depth of remission, with the goal of treatment advancing towards a cure for some patients. Accordingly, clinical endpoints must evolve to capture these outcomes, and to provide faster access to novel therapies. Minimal residual disease (MRD) is an important endpoint representing more accurately the depth of remission than complete response (CR), and is highly prognostic of progression-free survival (PFS) and overall survival (OS). MRD could be considered a key outcome of clinical trials and, as a surrogate for PFS, could identify the most cost-effective and durable treatment sequencing. MRD testing could also determine which patients would benefit from additional therapy and, accordingly, ascertain when therapy should be stopped earlier, to reduce toxicity and increase treatment-free intervals. Our article discusses possible uses of MRD in the modern era of CLL, including its definition, measurement, and value as a surrogate endpoint in clinical trials, and its potential roles in clinical practice.

As a growing segment of the military, Native Americans are expected to increase enrollment in Department of Veterans Affairs (VA) healthcare. Currently, 20% of Native American veterans are aged 65-74, which means they served during the Vietnam era. This study explores the experiences of rural American Indian veterans from two Montana reservations with accessing VA health services. Utilizing detailed data obtained in focus group and individual interviews, we examine the experiences, attitudes, barriers and needs of rural Vietnam-era veterans. Analyses indicate that while Native American Vietnam-era veterans experienced a poor reception returning to the US after military service, they had more positive receptions in their home reservation communities. However, reintegration was often impeded by poor local opportunity structures and limited resources. As they have aged and turned to the VA for healthcare, these veterans have encountered barriers such as lack of information regarding eligibility and services, qualifying for care, excessive distances to health services, the cost of travel, and poor quality of assistance from VA personnel. Despite variations in their resources, tribal community efforts to honor veterans have begun to facilitate better access to healthcare. Focusing on the roles and importance of place-based resources, this study clarifies challenges and obstacles that Native American Vietnam-era veterans experience with accessing VA health services in rural, reservation communities. Additionally, findings show how tribal efforts are facilitating access as they begin to implement the 2010 agreement between the VA and Indian Health Services to better serve Native veterans.

Flavonoids are a large group of ubiquitous polyphenolic secondary metabolites in plants with a wide range of properties, including a widely reported anti-cancer effect. The present review focuses on the different known mechanisms partaking in said anti-tumour effects, with particular emphasis on breast cancer. Their structure and reactivity allows flavonoids to work as antioxidant agents and phyto-oestrogens, modulating oestrogen signalling and metabolism to induce an overall anti-proliferative response. Other effects include the ability of flavonoids to modulate the CYP1 (cytochrome P450 1) and ABC (ATP-binding cassette) protein families, involved in carcinogenesis and drug delivery respectively. They can also induce apoptosis and cell cycle arrest and regulate other signalling pathways involved in the development and progression of cancer. In conclusion, there is accumulating evidence on the versatility of flavonoids and the numerous activities contributing to their anti-tumour effect. The complex, yet effective, mechanism of action of flavonoids, together with their interesting pharmacological properties, is the basis for their potential application in breast and other cancers. This rationale has led to the current interest in the application of flavonoids, including clinical trials currently underway and the development of novel flavonoids with improved properties, which hold great promise for tackling breast cancer.

Introduction: Multiple response criteria have been proposed for the assessment of treatment response in lymphoma patients (pts). The Lugano 2014 criteria have been adopted as the current standard for response assessment in lymphoma (Cheson et al. J Clin Oncol 2014), incorporating 18F fludeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) into standard staging of FDG-avid lymphomas. For non-FDG avid lymphomas, and when PET is not available, Lugano criteria use bi-dimensional tumor measurements of up to six CT target lesions. The more recently proposed Response Evaluation Criteria in Lymphoma (RECIL) (Younes et al. Annals Oncol 2017) were developed based on the hypothesis that uni-dimensional measurements of up to three target lesions could be used to assess response at a similar level of accuracy to the Lugano criteria. The prognostic value of Lugano 2014 versus RECIL 2017 criteria has not yet been assessed in large clinical trials. We compared the prognostic performance of Lugano and RECIL criteria in pts from the Phase III GOYA study (NCT01287741), which compared the efficacy of obinutuzumab (GA101, G) and rituximab (R) in combination with CHOP (G-CHOP vs R-CHOP) in previously untreated pts with CD20-positive DLBCL. Methods: In the GOYA study, pts were randomized 1:1 to receive either G-CHOP or R-CHOP (stratification factors: number of planned chemotherapy cycles, International Prognostic Index [IPI], and geographic region). FDG-PET scans were mandatory at sites where a PET scanner was available and were performed at screening and 6-8 weeks after the last study treatment. Response was assessed prospectively based on Cheson 2007 criteria and retrospectively according to standard Lugano 2014 criteria. A retrospective analysis based on RECIL 2017 criteria was also performed. Response categories by RECIL criteria were cross-tabulated against those by Lugano criteria. Estimates of the treatment effect were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) using stratified log-rank tests. The impact of covariates on PFS and OS were analyzed using a multivariate Cox model. Landmark analyses of PFS and OS according to end of treatment (EoT) complete response (CR)/non-CR status were performed, and the prognostic value of response at EoT was compared for the two methods. Results: Of the 1418 pts (intention-to-treat [ITT] population) in the GOYA study, 1334 had PET data and were evaluable for this analysis. Good agreement between Lugano and RECIL criteria was observed for EoT CR status, with 894/966 (92.5%) pts with a complete metabolic response (CMR) by Lugano classified as CR by RECIL (Table). However, 40/63 (63.5%) pts with progressive metabolic disease (PMD) at EoT according to Lugano criteria had a partial response (PR) or minor response (MR) by RECIL criteria, showing poor agreement for these variables. Of the 43 pts with PMD by Lugano and non-PD by RECIL at EoT, 15 pts had no PFS event by Lugano as assessed by CT and could be considered false positives. Concordance for PFS by CT was high between the two criteria, with a kappa estimate of 0.77 (95% CI: 0.74, 0.80). EoT CR status by RECIL was highly prognostic for PFS (stratified HR, 0.32; 95% CI: 0.25, 0.43; p Conclusions: EoT CR status according to RECIL 2017 criteria showed a high concordance with CMR status by Lugano 2014 criteria and was highly prognostic for PFS and OS in previously untreated DLBCL; however, discordance was seen for the identification of PD by RECIL compared with Lugano criteria. PFS as assessed by CT by RECIL, based on uni-dimensional size measurements of up to three target lesions, showed high concordance with PFS by Lugano criteria, based on bi-dimensional size measurements of up to six target lesions. Table Disclosures Kostakoglu: F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Martelli:F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sehn:Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria. Trněný:Amgen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy. Vitolo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Knapp:F. Hoffmann-La Roche Ltd: Employment. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Sahin:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Sellam:Roche: Employment, Equity Ownership. Ward:Hoffmann La Roche: Employment, Equity Ownership. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated for the following: in combination with chlorambucil, for the treatment of patients with previously untreated CLL; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with FL who relapsed after, or are refractory to, a rituximab-containing regimen; in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III or IV FL.

Introduction: The use of PET-CR as a surrogate endpoint would expedite the development of novel therapies and enable better estimates of sample size based on early outcomes of a trial. Previous studies have reported an association between end-of-therapy (EOT) PET results and long-term progression-free (PFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) patients receiving standard first-line chemoimmunotherapy. We have also previously shown that the overall predictability of PET-CR for PFS and OS in these trials is similar to that in 18 literature-based studies. (15-ICML 2019, P195). To assess the potential for PET-CR as a surrogate endpoint in registration trials, we conducted a prospectively designed individual patient-level-data meta-analysis of available clinical trials. Methods: We synthesized patient-level data from three prospective phase II and III trials (GOYA [NCT01287741], GATHER [NCT01414855], MAYO [NCT00670358]) conducted in previously untreated DLBCL patients, using a Bayesian hierarchical model. We considered the two treatment arms in GOYA (GOYA-R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] and GOYA-G-CHOP [obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone]) separate; hence a total of four arms, excluding patients without baseline PET scans. We investigated the relationship between PET-CR and long-term survival outcomes overall and within patient subgroups. We used Kaplan-Meier plots to compare survival endpoints by PET-CR status. We considered hypothetical RCTs that have PET-CR and PFS as endpoints to show how our model of the relationship between PET-CR and PFS can be used to predict the trial outcome. Results: We included 1496 patients (GOYA-R, GOYA-G, GATHER, MAYO, respectively: 665, 669, 100, 62). EOT PET-CR status was determined by the Lugano criteria in GOYA and by IHP in the other two studies. The overall rate of PET-CR was 72%; respectively 72%, 73%, 62% and 74% per arm. Panel A of the Figure shows Kaplan-Meier plots of PFS by PET-CR status. The Bayesian modeled hazard ratio (HR) comparing PET-CR versus nonCR was 0.13 (95% CI: 0.10, 0.15). The model can be used in planning a clinical trial as follows. Suppose a new therapy improves the PET-CR rate from 70% to 85%. Based on our model the expected HR for PFS treatment effect would be 0.71 (95% CI: 0.58, 0.84). The trial sample size required to demonstrate such an improvement with 90% power is about 650 patients, assuming an accrual rate of 50 patients per month and a minimum follow-up time of 12 months. Panel B of the Figure shows the model-based PFS HR and its CI (shaded) as it depends on the PET-CR rate of the new therapy. This plot also shows the estimated total trial sample size (in red), again assuming the relationship between PET-CR and PFS in our model. However, our model may not apply for the new therapy; and the trial could have an adaptive design with final sample size tailored to the accruing information about PET-CR and PFS and their relationship for the therapies in the trial. Conclusions: Achieving an EOT PET-CR in newly diagnosed DLBCL is highly predictive of favorable outcome in the populations we considered. The estimated HR is 0.13 for PFS, PET-CR versus nonCR, and it is 0.10 for OS. Based on our model, a treatment that improves PET-CR rate could be reasonably expected to have a benefit on PFS and OS, for the populations we considered. Whether a new therapy, with a different mechanism of action, that improves PET-CR rate will extend PFS in a clinical trial is less clear. An adaptive trial could be initiated based on our model as a hypothesis. This hypothesis can be verified or updated using accruing information in the trial itself. Our model can also help in planning clinical trials for re-estimating sample size during the trial and considering early stopping for futility. Further work should investigate the applicability of PET-CR in predicting PFS and/or OS for treatments that have different mechanisms of action and for other populations of patients. Acknowledgements: This work was funded by Genentech/Roche. Disclosures Berry: Berry Consultants, LLC: Consultancy, Employment, Equity Ownership, Other: Berry Consultants, LLC is a company that provides statistical design and analysis services to pharmaceutical companies (including Genentech/Roche), medical device companies, U.S. NIH cooperative groups, patient advocacy groups, and international consortia. Broglio:Berry Consultants LLC: Employment. Ward:Hoffmann La Roche: Employment, Equity Ownership. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Sahin:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. McGlothlin:Berry Consultants, LLC: Consultancy, Employment. Elliott:Berry Consultants, LLC: Employment. Sehn:Lundbeck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Trněný:Abbvie: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Vitolo:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau. Martelli:Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kostakoglu:F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Nowakowski:F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding.

Current design methods such as appropriate technology, human-centered design, and participatory design are intended to generate development projects that resonate with users in communities in developing countries. These approaches are extremely useful, but often lack adequate documentation about how to collect data on and incorporate users feedback into the project’s design. To address this gap, we introduced social science research methods into a service-learning course for undergraduate engineering students, which culminated in a trip to the communities for whom they were designing, to help students incorporate user feedback into the design of their projects. This paper documents our efforts. One of the main findings from a survey administered to students enrolled in the service-learning course indicate that students exhibited greater awareness of the users’ needs, rather than the technical specifications of their projects, after their on-site visit and interviews with users in the community. We conclude by identifying ways students were successful and plans for improving the integration of instruction about social science research methods into the engineering course.

Recently, Chief Dull Knife College, the tribal college of the Northern Cheyenne Nation, took new actions to assert sovereignty in relation to reservation schooling. This case study presents an account of these actions, which illustrates the kind of resistance that Hall and Fenelon suggest is possible in tribal college settings. Specifically, as a result of math curriculum reform at the Chief Dull Knife College, student success in math increased. Moreover, unintended consequences include that Northern Cheyenne student identities have been strengthened; college instructors use more culturally relevant strategies; and the tribal college has assumed a new leadership role in improving local schooling.

Purpose – The purpose of this paper is to share the challenges of, and learning gained by a voluntary sector organisation, Coventry Rape and Sexual Abuse Centre (CRASAC) in providing integrated care to victims of sexual violence. Design/methodology/approach – The paper first considers the big picture, focusing on the current UK public sector commissioning environment, the policy commitment to integrated care, and challenges a current focus on definitions of integration that do not consider wider determinants of health and well-being. As an example of client groups who may not meet narrow criteria, but require person centred coordinated care, the needs of victims of sexual violence are explored, illustrated by a case study within CRASAC. Findings – Challenges faced by CRASAC include identifying responsibility for specialist commissioning, maintaining strategic partnerships and a lack of cross-sector understanding of the needs of victims of sexual violence. Key learning points are the need to form strategic alliances and partnerships, to lobby and influence decision makers, to develop monitoring tools that demonstrate impact on long-term client outcomes and to constantly raise awareness of the needs of victims of sexual violence. Final reflections focus on the questions these issues raise for the future of specialised integrated care in the voluntary sector. Originality/value – The paper is of value to commissioners in health, social care and the criminal justice system, in addition to providers of services that are in contact with victims of sexual abuse. These include health, criminal justice, education, police and social care, alongside other voluntary and community sector organisations.

// James Meehan 1 , Carol Ward 1 , Arran Turnbull 1 , Jimi Bukowski-Wills 2 , Andrew J. Finch 2 , Edward J. Jarman 1 , Chrysi Xintaropoulou 1 , Carlos Martinez-Perez 1 , Mark Gray 1 , Matthew Pearson 3 , Peter Mullen 4 , Claudiu T. Supuran 5 , Fabrizio Carta 5 , David J. Harrison 4 , Ian H. Kunkler 1 and Simon P. Langdon 1 1 Cancer Research UK Edinburgh Centre and Division of Pathology Laboratory, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom 2 Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom 3 IGMM Advanced Imaging Resource, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom 4 School of Medicine, University of St Andrews, Fife KY16 9TF, United Kingdom 5 Department of Neurofarba, Sez. Chimica Farmaceutica e Nutraceutica, University of Florence, Sesto Fiorentino 50019, Italy Correspondence to: James Meehan, email: J.Meehan@sms.ed.ac.uk Keywords: carbonic anhydrase IX, NHE1, V-ATPase, breast cancer, hypoxia Received: April 14, 2016 Accepted: March 15, 2017 Published: April 17, 2017 ABSTRACT Hypoxic cancer cells exhibit resistance to many therapies. This study compared the therapeutic effect of targeting the pH regulatory proteins (CAIX, NHE1 and V-ATPase) that permit cancer cells to adapt to hypoxic conditions, using both 2D and 3D culture models. Drugs targeting CAIX, NHE1 and V-ATPase exhibited anti-proliferative effects in MCF-7, MDA-MB-231 and HBL-100 breast cancer cell lines in 2D. Protein and gene expression analysis in 2D showed that CAIX was the most hypoxia-inducible protein of the 3 targets. However, the expression of CAIX differed between the 3 cell lines. This difference in CAIX expression in hypoxia was consistent with a varying activity of FIH-1 between the cell lines. 3D expression analysis demonstrated that both CAIX and NHE1 were up-regulated in the hypoxic areas of multicellular tumor spheroids. However, the induction of CAIX expression in hypoxia was again cell line dependent. 3D invasion assays conducted with spheroids showed that CAIX inhibition significantly reduced the invasion of cells. Finally, the capability of both NHE1 and CAIX inhibitors to combine effectively with irradiation was exhibited in clonogenic assays. Proteomic-mass-spectrometric analysis indicated that CAIX inhibition might be combining with irradiation through stimulating apoptotic cell death. Of the three proteins, CAIX represents the target with the most promise for the treatment of breast cancer.

International educational opportunities for engineering students include, but are not limited to, internships, study abroad programs, and humanitarian programs such as Engineers Without Borders. Since 2007, a two-semester Global Engineering Outreach course at Brigham University has enabled engineering and technology students from multiple disciplines to design and implement humanitarian-based engineering projects. Energy, water, sanitation, and health projects have been implemented in Tonga, Ghana, and Peru. Currently, the projects focus on the needs of communities in Peru. Typically, nearly half of the students in the two-semester course speak and write Spanish fluently and have lived abroad in a Spanish-speaking country. This allows students to regularly engage with their Peruvian counterparts during the two semesters via phone and email exchanges on a near-weekly basis. An important aspect of the regular contact is the need to establish relationships and to obtain feedback and input from the community regarding the project. This work presents an overview of product development in relationship to the effectiveness of community engagement between the student development team and the Peruvian counterparts. In addition, strategies to foster community engagement will be discussed. Such strategies include workshops, resource development and investigation, design constraints and reviews, in-country communication, and an implementation trip.

Purpose This study aims to provide a better understanding of Native American women veterans’ experiences with Veteran Administration and Indian Health Services. Eighteen interviews were conducted with special attention to the quality and quantity of health and mental health care services veterans accessed, the barriers and local contextual factors in accessing and utilizing services, and potential solutions to service gaps for women veterans from two Montana reservations, the Northern Cheyenne Reservation and the Confederated Salish and Kootenai Tribes of the Flathead Reservation. Methodology/approach We examine the barriers and needs of Native American veterans in both reservations using qualitative methods. The research analyzed 18 interviews with women veterans from the Northern Cheyenne and Flathead reservations. Findings Native American women veterans identified a number of barriers to accessing care, some of which include lack of information regarding eligibility and the types of services available. Women often found the application process to be confusing and difficult. Other barriers included distance, cost of travel, and conflicts with their work schedule. Research limitations/implications This exploratory case study served to clarify the challenges and obstacles Native American women veterans experience with accessing health and mental health services. This research revealed several patterns and themes in the experience of Native American women veterans in both reservation communities when attempting to access and seek care at Veterans Administration (VA) facilities and Indian Health Services (IHS). This research calls for policy changes and research to clarify how resources can be more efficiently and effectively distributed to rural veterans. Originality/value Little research has addressed the needs of Native American veterans. American Indians and Alaska Natives serve at a higher rate in the U.S. military than any other population. This research provides important information about Native American veterans who are often underrepresented in survey research, yet a rapidly growing segment of the United States military and veteran population.

Radiation and drug resistance remain major challenges and causes of mortality in the treatment of locally advanced, recurrent and metastatic breast cancer. Metabolic reprogramming is a recently recognised hallmark of cancer with the hypoxic acidic extracellular environment as a major driver of invasion and metastases. Nearly 40% of all breast cancers and 50% of locally advanced breast cancers are hypoxic and their altered metabolism is strongly linked to resistance to radiotherapy and systemic therapy. The dependence of metabolically adapted breast cancer cells on alterations in cell function presents a wide range of new therapeutic targets such as carbonic anhydrase IX (CAIX). This review highlights preclinical approaches to evaluating an array of targets against tumour metabolism in breast cancer and early phase clinical studies on efficacy. © 2012 Elsevier Ltd.

We thank SULSA (Scottish Universities Life Science Alliance) for supporting this project through a SULSA BioSkape Industry PhD Studentship and Antoxis Limited for providing additional funding. We also thank the 7th Framework Programme of the European Union (METOXIA project; HEALTH-F2-2009-222741) for support. Background: The natural polyphenol myricetin induces cell cycle arrest and apoptosis in preclinical cancer models. We hypothesised that myricetin-derived flavonoids with enhanced redox properties, improved cell uptake and mitochondrial targeting might have increased potential as antitumour agents. Methods: We studied the effect of a second-generation flavonoid analogue, Oncamex, in a panel of 7 breast cancer cell lines, applying western blotting, gene expression analysis, fluorescence microscopy, and immunohistochemistry to xenograft tissue to investigate its mechanism of action. Results: Proliferation assays showed that Oncamex: treatment for 8 h reduced cell viability and induced cytotoxicity and apoptosis, concomitant with increased caspase activation. Microarray analysis showed that Oncamex was associated with changes in expression of genes controlling cell cycle and apoptosis . Fluorescence microscopy showed the compound’s mitochondrial targeting and ROS-modulating properties, inducing superoxide production at concentrations associated with anti-proliferative effects. A preliminary in vivo study in mice implanted with the MDA-MB-231 breast cancer xenograft showed that Oncamex inhibited tumour growth, reduced tissue viability and Ki-67 proliferation, with no overall systemic toxicity. Conclusion: Oncamex is a novel flavonoid capable of specific mitochondrial delivery and redox modulation. It has shown antitumour activity in preclinical models of breast cancer, supporting the potential of this prototypic candidate for its continued development as an anticancer agent. Publisher PDF

Qualitative data from16 offenders were analyzed to understand the process of reintegration from their perspective. The offenders identified six factors that they felt influenced their ability to reintegrate and desist from crime: (1) substance abuse; (2) employment; (3) family support; (4) types of friends; (5) personal motivation to change; and (6) age. A large majority indicated that drug abuse was a major contributor to their criminal activities. Most said supports from family, friends, and treatment services were important for successful reintegration. Those who were successful tended to have both a personal desire to change and a support system that helped them reintegrate and desist from drug use and crime. Support had more impact among those who desired to change and those who received support were more likely to perceive that change is possible.

A series of 50 sulfamates were obtained by reacting 4-aminophenol with isocyanates followed by sulfamoylation. Most of the new compounds were nanomolar inhibitors of the tumor-associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII, whereas they inhibited less cytosolic offtarget isoforms CA I and II. Some of these sulfamates showed significant antiproliferative activity in several breast cancer cell lines, such as SKBR3, MCF10A, ZR75/1, MDA-MB-361 and MCF7, constituting interesting anticancer leads.

Factors related to dropping out of school are examined among a rural population of American Indians in southeastern Montana. Analyses assess the relative effects of community location, type of school, and student, family, and school variables on dropout behavior. Findings reveal the importance of students' community residence, parental education, and school experiences. The effects of these factors vary by school, however, suggesting that schools create different environments, opportunities, and relationships with specific communities that affect school outcomes. This research suggests the need to examine interactions among schools and Indian students, their families, and communities to understand school dropout patterns.

Living in poverty is associated with high levels of protracted stress associated with health problems. Economic and food insecurity are particularly poignant aspects of poverty and condition the work of securing basic daily needs of families. Recent studies suggest that levels of stress increase as family food needs rise. This paper presents new findings which clarify the relationship of food provisioning to stress levels, by examining actual food provisioning strategies and food insecurity among the Northern Cheyenne Indians of southeastern Montana. Results clearly show that stress varies by types of food acquisition strategies. Contrary to our expectations, more complex strategies, including relatively unpredictable and cumbersome food provisioning activities, are not linked to higher stress levels in our analysis. Controlling for food security levels, households using a combination of local programs and informal subsistence sources are the least stressed, despite the demands of managing a large number of food sources. Households primarily using Food Stamps are the most likely to experience high levels of stress. Interviews with Food Stamp recipients show that potential sources of stress include inadequate allocations of Food Stamps, difficulty achieving and maintaining eligibility, challenges to complying with paperwork and appointment requirements, as well as personal obstacles and community barriers to making food stamps last. Analyses indicate that contradictions between local cultural norms for food provisioning and the realities of food insecurity in this context promote strategies emphasizing greater independence from federal food programs.

Focus group research needs to be modified when the focus groups are to be conducted in a rural area or with a rural population. The authors argue for “seeing the rural”: for recognizing rurality as a social context that affects research. Based on experience with North American rural focus groups, the authors propose six aspects of the design of rural focus groups in which rurality should be taken into account: conceptualizing the rural place, identifying research participants, inviting residents to participate in a focus group, selecting a site for the focus group and scheduling it, conducting the focus group, and expressing appreciation. The article ends with an empirical investigation evaluating selected rural focus group recruitment strategies.

OBJECTIVE Certified Peer Specialist training initiatives leading to paid peer support positions are increasing nationally. This longitudinal study examines a comprehensive set of outcomes associated with such an initiative undertaken in Pennsylvania beginning in 2004. METHODS Certified Peer Specialist Training participants in three regions of Pennsylvania responded to a 60-item, multiple choice knowledge test based on the Certified Peer Specialist training curriculum. Additionally, these individuals were asked to provide permission to be contacted up to one year after completing the program to obtain employment information related to their experience as a certified peer specialist. RESULTS Ninety-seven percent of the trainees successfully completed the program with a 22% increase in knowledge. Eighty-two percent were working one year later. Peer specialists were very satisfied with their employment; felt accepted by co-workers and reported receiving good, but infrequent supervision. CONCLUSIONS The results suggest that these initiatives can be successfully implemented, although greater attention is needed to ensure that new jobs are being created for trainees and that they are being properly supervised like all other employees.

Utilizing ethnographic research methods, this case study examines the experiences of an NGO-sponsored health care program in rural Mali. The findings indicate that while, in principle, the organization operates from an alternative development base, it has been unable to decentralize the decision-making process and facilitate community dialogue and participation. Numerous problems resulted, including superficial forms of local participation, lack of community ownership, non-remuneration of health workers and midwives, inadequate training, and ultimately, limited program gains. The analyses highlight the complexity and dynamic nature of health program implementation in a developing context, and suggest several factors important to project success. These include drawing on diverse local perspectives, promoting broad-based participation, and providing culturally appropriate ways to include all community members, particularly women.

The role of radiotherapy is well established in the multidisciplinary management of breast cancer. However, its use could be customised further with the intent of enhancing tumour cell radiosensitisation and reducing normal cell toxicity. The importance of tumour heterogeneity and the microenvironment in the response to radiotherapy is under intense scrutiny and the value of molecular profiling is being increasingly recognised. Genome Wide Association Studies are likely toplay an important role in elucidating the molecular pathogenesis of radiotoxicity in the emerging area of radiogenomics. Biomarkers of tumour radiosensitivity should help indicate potentially responsive and unresponsive cancers. Further understanding of the tumour microenvironment and better preclinical models will help identify targets to enhance radiosensitivity or reverse radioresistance.

Using data from a 2001 survey of a representative sample of Northern Cheyenne reservation residents, this paper examines use of a variety of food sources, nutritional health and risk factors, diabetes risk factors, and food insecurity. Results indicate that substantial proportions of the respondents had high levels of nutritional risk, food insecurity, and diabetes risk. Importantly, those using community emergency food sources and informal economic strategies to meet food shortages were more likely to be food insecure. Those with higher nutritional risk and lower nutritional health were also more likely to be food insecure. Finally, being younger, educated and using wages to obtain food increased the risk for diabetes.

Recent innovations in breast cancer radiotherapy include intensity modulated radiotherapy, brachytherapy and intraoperative radiotherapy and current trials are seeking to evaluate their value in optimizing local control while maintaining cosmetic effects. Future clinical dividends in local control and survival may come from the identification of molecular signatures of breast cancer radiosensitivity, the development of predictive signatures and identification of immunohistochemical markers of risk of local recurrence. The importance of tumour heterogeneity is being increasingly recognized as an important factor in determining radiotherapy response and an improved understanding of the biology of the tumour microenvironment may identify targets that allow enhanced radiosensitisation or reversal of radioresistance when inhibited. This review describes recent developments in these areas.

// Carol Ward 1 , James Meehan 1 , Peter Mullen 2 , Claudiu Supuran 3 , J. Michael Dixon 4 , Jeremy S. Thomas 5 , Jean-Yves Winum 6 , Philippe Lambin 7 , Ludwig Dubois 7 , Nanda-Kumar Pavathaneni 6, 7 , Edward J. Jarman 1 , Lorna Renshaw 4 , InHwa Um 2 , Charlene Kay 1 , David J. Harrison 2 , Ian H. Kunkler 8 , Simon P. Langdon 1 1 Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom 2 School of Medicine, University of St Andrews, North Haugh, St Andrews, United Kingdom 3 Universita degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino, Florence, Italy 4 Edinburgh Breast Unit, Western General Hospital, Edinburgh, United Kingdom 5 Department of Pathology, Western General Hospital, Edinburgh, United Kingdom 6 Institut des Biomolecules Max Mousseron (IBMM), UMR 5247, CNRS-UM1-UM2, Batiment de Recherche Max Mousseron, Ecole Nationale Superieure de Chimie de Montpellier, Montpellier, France 7 Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands 8 Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom Correspondence to: Carol Ward, e-mail: drcward@hotmail.co.uk Keywords: carbonic anhydrase IX, breast cancer, tumour microenvironment, invasion, hypoxia Received: May 11, 2015 Accepted: June 22, 2015 Published: July 04, 2015 ABSTRACT Triple negative, resistant or metastatic disease are major factors in breast cancer mortality, warranting novel approaches. Carbonic anhydrase IX (CAIX) is implicated in survival, migration and invasion of breast cancer cells and inhibition provides an innovative therapeutic strategy. The efficacy of 5 novel ureido-substituted sulfamate CAIX inhibitors were assessed in increasingly complex breast cancer models, including cell lines in normoxia and hypoxia, 3D spheroids and an ex-vivo explant model utilizing fresh biopsy tissue from different breast cancer subtypes. CAIX expression was evaluated in a tissue microarray (TMA) of 92 paired lymph node and primary breast cancers and 2 inhibitors were appraised in vivo using MDA-MB-231 xenografts. FC11409B, FC9398A, FC9403, FC9396A and S4 decreased cell proliferation and migration and inhibited 3D spheroid invasion. S4, FC9398A and FC9403A inhibited or prevented invasion into collagen. FC9403A significantly reversed established invasion whilst FC9398A and DTP348 reduced xenograft growth. TMA analysis showed increased CAIX expression in triple negative cancers. These data establish CAIX inhibition as a relevant therapeutic goal in breast cancer, targeting the migratory, invasive, and metastatic potential of this disease. The use of biopsy tissue suggests efficacy against breast cancer subtypes, and should provide a useful tool in drug testing against invasive cancers.

Many cancer cells rely on aerobic glycolysis for energy production and targeting of this pathway is a potential strategy to inhibit cancer cell growth. In this study, inhibition of five glycolysis pathway molecules (GLUT1, HKII, PFKFB3, PDHK1 and LDH) using 9 inhibitors (Phloretin, Quercetin, STF31, WZB117, 3PO, 3-bromopyruvate, Dichloroacetate, Oxamic acid, NHI-1) was investigated in panels of breast and ovarian cancer cell line models. All compounds tested blocked glycolysis as indicated by increased extracellular glucose and decreased lactate production and also increased apoptosis. Sensitivity to several inhibitors correlated with the proliferation rate of the cell lines. Seven compounds had IC50 values that were associated with each other consistent with a shared mechanism of action. A synergistic interaction was revealed between STF31 and Oxamic acid when combined with the antidiabetic drug metformin. Sensitivity to glycolysis inhibition was also examined under a range of O2 levels (21% O2, 7% O2, 2% O2 and 0.5% O2) and greater resistance to the inhibitors was found at low oxygen conditions (7% O2, 2% O2 and 0.5% O2) relative to 21% O2 conditions. These results indicate growth of breast and ovarian cancer cell lines is dependent on all the targets examined in the glycolytic pathway with increased sensitivity to the inhibitors under normoxic conditions.

This paper examines the effectiveness of an NGO-sponsored literacy program in rural Mali. The study employs ethnographic techniques to examine the type of literacy instruction provided, the level of participation, the meanings of literacy to participants, and the contextual factors that influence the social and personal effects of literacy. The analyses reveal that the program has been more advantageous for men, particularly in terms of opportunities for the use of literacy skills. Oversight of the cultural context combined with programmatic challenges including failure of the NGO to meet its own critical literacy goals have limited women's ability to access and derive benefits from the literacy program.

A subset of leukocytes, known as the granulocytes, are the bodys first line of innate immune defense. The granulocytes are comprised of neutrophils, eosinophils and basophils of which the former two will be the focus of this review. Neutrophils defend the body against bacterial and fungal infection whilst eosinophils are thought to defend against parasitic invasions. Granulocytes are recruited to the site of infection or tissue damage where their relatively short half-life can be extended by regulatory external factors including hypoxic environments or agents that activate signaling pathways, such as NF-kB which is implicated in the up-regulation of anti-apoptotic genes. Granulocytes release various proteins, proteolytic enzymes and toxic oxygen products into the phagolysosome or surrounding environment destroying the invading organism. However, in order for inflammation to be resolved it is essential that granulocytes die by apoptosis and are phagocytosed by macrophages in a non-inflammatory fashion. This prevents the release of the cells histotoxic contents into the extracellular milieu thereby reducing the potential for tissue damage. In instances when granulocytes fail to appropriately enter apoptosis or a defect in phagocytic clearance occurs the inflammatory response can be perpetuated, potentially resulting in the development and promotion of inflammatory disorders such as asthma or rheumatoid arthritis. Thus, selective enhancement of apoptosis and augmentation of macrophage clearance could allow targeting of inflammatory resolution to provide potential novel therapeutic agents for the treatment of inflammatory disorders.

Lipopolysaccharide (LPS) induces a marked delay in human neutrophil apoptosis that is reversed by the anti-inflammatory cytokine IL-10. The effect of IL-10 is specific since other agents that delay neutrophil apoptosis are not affected. To investigate mechanisms underlying the actions of IL-10, we examined signaling pathways activated by LPS per se and in response to IL-10. The MAPK kinase (MEK) 1 inhibitor PD098059, the protein kinase C (PKC) inhibitor Ro31,8220, and the phosphatidylinositol-3 kinase (PI3-K) inhibitor LY294002 all partially reversed LPS-mediated retardation of neutrophil apoptosis, but the p38 MAPK inhibitor SB203850 did not. LPS activates the transcription factor NF-kappaB, however, IL-10 did not affect the ability of LPS to activate NF-kappaB as assessed by IkappaB-alpha proteolysis. Although IL-10 did not alter activation of ERK by GM-CSF or TNF-alpha, it did inhibit activation induced by LPS. Thus our data illustrate that LPS-induced neutrophil survival is regulated by the MAPK, PKC and PI3-K pathways as well as NF-kappaB, and can be reversed by IL-10, through a mechanism involving inhibition of ERK activation. Because of the specific nature of this inhibition, we conclude that IL-10 interferes with an ERK activation pathway, which is not involved in GM-CSF or TNF-alpha signaling.

The accumulation of neutrophils during inflammation is essential for the destruction and removal of invading microorganisms. However, for resolution of inflammation to occur, neutrophils must also be removed from the inflammatory site since these cells are capable of releasing tissue toxic molecules. Neutrophil removal has been shown to occur via apoptosis and phagocyte clearance of apoptotic cells. Therefore, manipulation of these processes is likely to be a key therapeutic strategy in the management of inflammatory disease. In this review, we examine mediators of neutrophil survival and apoptosis and the signalling pathways that regulate the balance between life and death in these cells.

The World Bank estimates that 78% of economically active women in Mali are engaged in agricultural activities. Consequently women are challenged as much as men by recent changes that have resulted in diminished agricultural yield. Importantly this situation has increased male migration to urban centers to find alternative work making women’s roles in production essential to household and community survival. Attempting to ensure food sufficiency women supplement family earnings through small-scale income-generating activities such as the production of charcoal the processing of shea butter and market gardening. In his study on Mali Becker (2000) found that revenue from own-account activities including gardening are essential to food security and most critical for women whose access to labor and insecure land tenure were most volatile. The failure of large-scale agricultural interventions has also prompted scholars to propose alternative strategies for enhancing food security including small-scale gardens. Several facets of community gardening such as the relatively low start-up cost adaptability to harsh conditions and the capacity for fostering sound environmental practices have been the basis for its support by NGOs worldwide. Unlike subsistence farming which is relatively more labor intensive gardening activities can coincide with women’s daily tasks. Some scholars further argue that gardening is a “food-based” strategy that can empower women because it relies on existing practices and on their responsibility as caregivers. (excerpt)

Human granulocytes clearly play an important role in host defence against invading organisms, however they have also been implicated in the pathogenesis and progression of many chronic inflammatory diseases. In addition, these cells have been paramount in gaining a better understanding of many key-signalling pathways regulating fundamental biological processes. Since granulocytes are terminally differentiated and undergo relatively rapid constitutive apoptosis it has been difficult to manipulate intracellular events by transfection or transduction procedures. It has been shown in recent years that the HIV-TAT protein transduction system can be successfully used in granulocytes to manipulate key signalling mechanisms regulating functional responsiveness and survival. In this paper, we review recent literature highlighting important developments using this system in isolated human granulocytes and in inflammatory process in vivo where these cells play a prominent role.

The 6th World Congress on Inflammation was held in the Vancouver Convention and Exhibition Center. This biennial meeting was organised by the Inflammation Research Association (USA) and Triangle 3 Ltd (UK), under the auspices of the International Association of Inflammation Societies. This meeting aimed to promote international cooperation amongst inflammation scientists and provide a communication network for various inflammation societies from around the world. The conference covered the most up-to-date concepts in inflammation, new drugs and treatments, and advances in cell biology. However, there were some topics which were either novel to many attendees or which provided links to a number of presentations, thus underlining their importance. The following is by no means an exhaustive review, but merely reflects the authors' interests.

Objectives:To describe the conceptual framework and methodology of the Evaluation of Processes and Indicators in Infection Control (EPIC) study and present results of CVC insertion characteristics and organizational practices for preventing BSIs. The goal of the EPIC study was to evaluate relationships among processes of care, organizational characteristics, and the outcome of BSI.Design:This was a multicenter prospective observational study of variation in hospital practices related to preventing CVC-associated BSIs. Process of care information (eg, barrier use during insertions and experience of the inserting practitioner) was collected for a random sample of approximately 5 CVC insertions per month per hospital during November 1998 to December 1999. Organization demographic and practice information (eg, surveillance activities and staff and ICU nurse staffing levels) was also collected.Setting:Medical, surgical, or medical-surgical ICUs from 55 hospitals (41 U.S. and 14 international sites).Participants:Process information was obtained for 3,320 CVC insertions with an average of 58.2 (± 16.1) insertions per hospital. Fifty-four hospitals provided policy and practice information.Results:Staff spent an average of 13 hours per week in study ICU surveillance. Most patients received nontunneled, multiple lumen CVCs, of which fewer than 25% were coated with antimicrobial material. Regarding barriers, most clinicians wore masks (81.5%) and gowns (76.8%); 58.1% used large drapes. Few hospitals (18.1%) used an intravenous team to manage ICU CVCs.Conclusions:Substantial variation exists in CVC insertion practice and BSI prevention activities. Understanding which practices have the greatest impact on BSI rates can help hospitals better target improvement interventions.

It has become apparent that the resolution of inflammation depends on the removal of unwanted inflammatory cells, a process governed by physiological apoptosis and non-inflammatory clearance of apoptotic cells. Granulocytes are central to many of the pathophysiological consequences of uncontrolled inflammatory reactions. Hemopoietic factors and cytokines play a critical role in regulating the longevity of these cells in vitro and in vivo. Here we review the progress that has been made in the understanding of granulocyte apoptosis and the implications for immunotherapy and pharmacological strategies in the treatment of allergic inflammatory diseases for therapeutic gain.

The field of apoptosis has expanded to include research in almost all subject areas of cell biology. Despite this growth, there are still many unanswered questions, some of which are fundamental to the development of therapeutic strategies. Most importantly, the underlying mechanisms involved in conferring specificity of apoptotic signals must be determined. This will allow the development of treatments to delete injured or transformed cells and minimize damage to other tissues. Such information is also necessary to combat degenerative diseases, to prevent critical loss of cells. In addition, it would be of therapeutic benefit to selectively induce apoptosis in specific cells where removal of unwanted cells is required (e.g. tumour cells in malignant tissue or inflammatory cells responsible for tissue damage in chronic inflammatory disease). Therefore we have to understand how the full complement of signalling pathways, and survival and apoptotic proteins determine the end effect of an apoptotic signal. Apoptotic cells are known to functionally influence phagocytes that ingest them, but little is known of the effect of apoptosis on neighbouring cells or of signals generated during the apoptotic process itself. Although the processes of mitosis and apoptosis would appear to be diametrically opposed, cell-cycle proteins are involved in apoptosis, and may be able to influence cell-death mechanisms; conversely, proliferation may be caspase-dependent in some cells. Further study is necessary to discover how these pathways are interlinked since such knowledge would be particularly useful in cancer treatment. The link between pathogen-survival strategies and apoptotic mechanisms will also reward further work. Viruses, in particular, exploit cellular survival and death pathways for replication purposes and may represent a targeting approach for specific treatments.

Since most inflammatory mediators that stimulate granulocyte responsiveness also delay apoptosis, it is often assumed that activation and longevity are causally related. Using isolated human peripheral blood neutrophils and eosinophils, we examined this association by exploiting the proinflammatory lipid mediators, the leukotrienes (LTs), and investigated granulocyte function and apoptosis. LTB4 induced elevation of intracellular free Ca2+ concentration ([Ca2+]i), cell polarisation and retardation of neutrophil apoptosis, although the antiapoptotic effect occurred only at concentrations 300 nM. LTB4-induced activation was attenuated by CP-105,696, a BLT1-specific antagonist suggesting classical LTB4 receptor BLT1 involvement. Despite demonstrating the presence of the neutrophil intracellular LTB4 receptor peroxisome-proliferator activator receptor-α (PPARα) in neutrophils, the selective PPARα agonist WY-14,643 did not mimic LTB4-induced prosurvival effects. LTB4-induced survival, however, also appeared to be mediated by BLT1 since CP-105,696 inhibited the LTB4-mediated antiapoptotic effect. Furthermore, based on studies with CP-105,696 and 5-lipoxygenase inhibitors, lipopolysaccharide (LPS)-, granulocyte–macrophage colony-stimulating factor (GM-CSF)-, dexamethasone- and dibutyryl-cAMP (db-cAMP)-induced delay of neutrophil apoptosis did not involve autocrine production of LTB4. Although LTB4 and LTD4 induced human eosinophil [Ca2+]i elevation and polarization, these LTs did not influence eosinophil apoptosis. Furthermore, LTB4- and LTD4-induced eosinophil activation was attenuated by CP-105,696 and the Cys-LT1 receptor antagonist montelukast, respectively, highlighting specific receptor dependency. Thus, mediator-triggered granulocyte activation and antiapoptotic pathways are distinct events that can be differentially regulated. British Journal of Pharmacology (2003) 139, 388–398. doi:10.1038/sj.bjp.0705265

Carbonic anhydrase IX has been under intensive investigation as a therapeutic target in cancer. Studies demonstrate that this enzyme has a key role in pH regulation in cancer cells, allowing these cells to adapt to the adverse conditions of the tumour microenviroment. Novel CAIX inhibitors have shown efficacy in bothin vitroandin vivopre-clinical cancer models, adversely affecting cell viability, tumour formation, migration, invasion, and metastatic growth when used alone. In co-treatments, CAIX inhibitors may enhance the effects of anti-angiogenic drugs or chemotherapy agents. Research suggests that these inhibitors may also increase the response of tumours to radiotherapy. Although many of the anti-tumour effects of CAIX inhibition may be dependent on its role in pH regulation, recent work has shown that CAIX interacts with several of the signalling pathways involved in the cellular response to radiation, suggesting that pH-independent mechanisms may also be an important basis of its role in tumour progression. Here, we discuss these pH-independent interactions in the context of the ability of CAIX to modulate the responsiveness of cancer to radiation.

The hypoxic areas of solid cancers represent a negative prognostic factor irrespective of which treatment modality is chosen for the patient. Still, after almost 80 years of focus on the problems created by hypoxia in solid tumours, we still largely lack methods to deal efficiently with these treatment-resistant cells. The consequences of this lack may be serious for many patients: Not only is there a negative correlation between the hypoxic fraction in tumours and the outcome of radiotherapy as well as many types of chemotherapy, a correlation has been shown between the hypoxic fraction in tumours and cancer metastasis. Thus, on a fundamental basis the great variety of problems related to hypoxia in cancer treatment has to do with the broad range of functions oxygen (and lack of oxygen) have in cells and tissues. Therefore, activation-deactivation of oxygen-regulated cascades related to metabolism or external signalling are important areas for the identification of mechanisms as potential targets for hypoxia-specific treatment. Also the chemistry related to reactive oxygen radicals (ROS) and the biological handling of ROS are part of the problem complex. The problem is further complicated by the great variety in oxygen concentrations found in tissues. For tumour hypoxia to be used as a marker for individualisation of treatment there is a need for non-invasive methods to measure oxygen routinely in patient tumours. A large-scale collaborative EU-financed project 2009-2014 denoted METOXIA has studied all the mentioned aspects of hypoxia with the aim of selecting potential targets for new hypoxia-specific therapy and develop the first stage of tests for this therapy. A new non-invasive PET-imaging method based on the 2-nitroimidazole [(18)F]-HX4 was found to be promising in a clinical trial on NSCLC patients. New preclinical models for testing of the metastatic potential of cells were developed, both in vitro (2D as well as 3D models) and in mice (orthotopic grafting). Low density quantitative real-time polymerase chain reaction (qPCR)-based assays were developed measuring multiple hypoxia-responsive markers in parallel to identify tumour hypoxia-related patterns of gene expression. As possible targets for new therapy two main regulatory cascades were prioritised: The hypoxia-inducible-factor (HIF)-regulated cascades operating at moderate to weak hypoxia (

This paper presents a case study of a rural credit program sponsored by the Ouelessebougou-Utah Alliance (OUA) in Mali, West Africa. Ethnographic methods are employed to determine the outreach, impact, and sustainability of the program. Findings indicate that program specifications increasingly limit participation to an established and primarily male clientele. Both male and female borrowers reported higher earnings and greater contribution to household expenses; however, access to credit for women is not associated with improved status. The prospect for administrative and financial sustainability of the program is undermined by a weak and ineffective educational component.

Many inflammatory mediators retard granulocyte apoptosis. Most natural PGs studied herein (e.g., PGE(2), PGA(2), PGA(1), PGF(2 alpha)) either delayed apoptosis or had no effect, whereas PGD(2) and its metabolite PGJ(2) selectively induced eosinophil, but not neutrophil apoptosis. This novel proapoptotic effect does not appear to be mediated via classical PG receptor ligation or by elevation of intracellular cAMP or Ca(2+). Intriguingly, the sequential metabolites Delta(12)PGJ(2) and 15-deoxy-Delta(12,) Delta(14)-PGJ(2) (15dPGJ(2)) induced caspase-dependent apoptosis in both granulocytes, an effect that did not involve de novo protein synthesis. Despite the fact that Delta(12)PGJ(2) and 15dPGJ(2) are peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activators, apoptosis was not mimicked by synthetic PPAR-gamma and PPAR-alpha ligands or blocked by an irreversible PPAR-gamma antagonist. Furthermore, Delta(12)PGJ(2) and 15dPGJ(2) inhibited LPS-induced I kappa B alpha degradation and subsequent inhibition of neutrophil apoptosis, suggesting that apoptosis is mediated via PPAR-gamma-independent inhibition of NF-kappa B activation. In addition, we show that TNF-alpha-mediated loss of cytoplasmic I kappa B alpha in eosinophils is inhibited by 15dPGJ(2) in a concentration-dependent manner. The selective induction of eosinophil apoptosis by PGD(2) and PGJ(2) may help define novel therapeutic pathways in diseases in which it would be desirable to specifically remove eosinophils but retain neutrophils for antibacterial host defense. The powerful proapoptotic effects of Delta(12)PGJ(2) and 15dPGJ(2) in both granulocyte types suggest that these natural products control the longevity of key inflammatory cells and may be relevant to understanding the control and resolution of inflammation.