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This study's focus is the association of end-of-therapy (EOT) PET results with progression-free (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma receiving first-line chemoimmunotherapy. We develop a Bayesian hierarchical model for predicting PFS and OS from EOT PET-complete response (PET-CR) using a literature-based meta-analysis of 20 treatment arms and a substudy of 4 treatment arms in 3 clinical trials for which we have patient-level data. The PET-CR rate in our substudy was 72%. The modeled estimates for hazard ratio (PET-CR/non-PET-CR) were 0.13 for PFS (95% CI 0.10, 0.16) and 0.10 for OS (CI 0.07, 0.12). Hazard ratios varied little by patient subtype and were confirmed by the overall meta-analysis. We link these findings to designing future clinical trials and show how our model can be used in adapting the sample size of a trial to accumulating results regarding treatment benefits on PET-CR and a survival endpoint.

Supplementary Figure 2 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Supplementary Figure 1 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Supplementary Figure 5 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Supplementary Figure 3 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Supplementary Figure 4 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Supplementary Methods, Legends for Figures 1-5 from WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

Multiple qualitative and quantitative studies have investigated homophobic language and its associated correlates. However, very few studies have approached this phenomenon from an ethnographic met...

Due to the increasing number of events around the world, event sustainability is an area of research relevant across disciplines. Research has found that event sustainability encompasses economic, environmental, and social legacies. However, events may face unforeseen challenges, sometimes even major scandals. How do these scandals impact residents and the sustainable legacy of the mega-event? As a historical case study, we explore social aspects of event sustainability in the wake of the 2002 Winter Olympics bid scandal, where it was reported that the Salt Lake Olympic Committee (SLOC) bribed members of the International Olympic Committee (IOC) to secure votes in favor of Salt Lake City hosting the 2002 Winter Olympic. Despite the bribery scandal, the Salt Lake City Games were considered a success by the media and members of the SLOC and IOC. Specifically, the present study investigates local residents’ perceptions of the scandal before, during, and after the Olympics using data gathered from 1999 to 2018 in Heber Valley, Utah. We find that time is a significant predictor of residents’ feelings toward the scandal. Further, feelings towards the Olympics, community desirability, race, and biological sex are also significant predictors. These findings lead us to conclude that the effects of the scandal on the Olympics’ sustainable legacy fade away over time.

Understanding how the lack of higher education opportunities due to geographic distance affects perceptions of communities and education is essential in creating sustainable education systems in rural areas. More specifically, this research examines how geographic distance and the absence of institutes, sometimes called an education desert, affect perceptions of community and the perceived value of education. We used data from the 2017 Rural Utah Community Study (RUCS) of residents living in twenty-five rural communities, with a sample size of 1286, and found that the proximity to different types of higher education, four- and two-year institutions, can significantly influence community well-being and the perceived value of education.

General education (GE) classes are designed to reflect the mission and goals of the university and to help students become more well-rounded, career-ready, and civically-minded post-graduation. Students’ perceptions of these courses have a significant influence on their capacity to succeed, and ultimately to get the most out of their college experience. Using results from an email questionnaire sent to students at a private university in the western United States, we analyze the relationships between perceptions of the GE experience, sense of community, and academic year, and we find that sense of community is positively associated with perceptions of GEs. These results also show freshmen having a higher sense of community than juniors or seniors, and that scholastic class in school is negatively associated with satisfaction with GEs. Furthermore, we find that seniors generally have a lower perception of the importance of GEs in their lives when compared to freshmen.

Background: Radiotherapy (RT) plays an important role in the multimodal treatment of breast cancer (BC). Despite improvements in the accuracy of delivering radiation to specific biological target volumes, the clinical response of BC to RT is still affected by intrinsic/acquired radioresistance. These resistant cancer cells can contribute to the development of recurrent disease and poor patient outcomes. Clinical signs of RT response are often not apparent for several weeks post-treatment; patients who fail to respond will therefore initially go undetected. There are currently no clinically validated biomarkers that can predict which patients will respond to RT or assess response during treatment. Our study aims to address this major clinical need through the identification and validation of biomarkers of radiation responsiveness. Methods: The effects of different radiation doses (2 - 10Gy) at a range of time points (1 - 24h) were investigated by analysing the protein secretion profiles from 3 BC cell lines: MCF-7 (ER+), ZR-751 (ER+) and MDA-MB-231 (ER-). Conditioned media was collected from each dose/time point and proteins isolated for mass spec analysis. For comparison, radioresistant models were derived from each of the 3 cell lines and were characterized by proliferation and colony formation assays, invasion and migration assays, whole-genome transcriptomic sequencing (WGTS) analysis and western blotting. To assess intrinsic response to RT a panel of 16 BC cell lines were evaluated by colony formation assays following a 2Gy dose of radiation. WGTS of a patient cohort of 230 (138 ER+ve, 92 ER-ve) post-menopausal women with BC, treated with breast conserving surgery and adjuvant RT but no systemic adjuvant therapy, with a median follow-up of 14 years, is currently underway. Results: 9 biomarkers emerged whose secretion was significantly increased with radiation. These were evaluated by western blotting of conditioned media 24h after a 2Gy dose of RT in matched radio-sensitive and resistant cell lines; this confirmed significantly higher levels of radiation induced secretion from sensitive cells compared to resistant. Radioresistant cell lines were characterised by epithelial-to-mesenchymal-transition, enhanced invasion/migration, loss of ER and PgR and increased EGFR and PI3K signaling activity. Initial mechanistic investigations suggest that biomarker release in response to radiation occurs via microvesicles. A blood-based assay to test the level of these secreted biomarkers is currently under development. Pre-treatment levels of the 9 biomarkers were also found to be associated with prediction of intrinsic response to RT at both gene and protein level. A gene expression signature comprising the 9 candidates is strongly associated with the intrinsic response to RT across the 16 BC cell lines studied, with higher expression found in those more sensitive to RT compared with those less sensitive or resistant. Validation of the predictive power of these biomarkers in terms of recurrence-free and overall BC specific survival is currently being assessed at gene and protein level in the patient cohort. Conclusions: We have identified 9 biomarkers which are released from BC cells sensitive to radiation 24h after a 2Gy dose (in line with current clinical standards) but not from radio-resistant derivatives.A blood based assay is currently under development which has the potential to monitor response to RT in the neoadjuvant and palliative settings.Intracellular levels of the 9 biomarkers are strongly associated with intrinsic response to RT and may hold predictive potential.These biomarkers may have the potential to improve patient care by identifying patients less likely to benefit from RT, paving the way for personalization of treatment, including altered dosing schedules and the future use of emerging radio-sensitizers. Citation Format: James Meehan, Mark Gray, Carlos Martinez-Perez, Charlene Kay, J Michael Dixon, Jimi Wills, Carol Ward, Alex von Kriegsheim, Niall Quinn, Olga Oikonomidou, David Cameron, Simon P Langdon, David Argyle, Ian H Kunkler, Arran K Turnbull. Development and validation of novel biomarkers of response to radiotherapy in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-18.

Researchers have often neglected the role of hopelessness in violent behavior during adolescence. Moreover, little research has examined this relationship over time. Using data from Waves I and II ...

Responding to identified needs for increased veterans’ access to healthcare, in 2010 the United States Department of Veterans Affairs (VA) launched the Veteran Community Partnership (VCP) initiative to “foster seamless access to, and transitions among, the full continuum of non-institutional extended care and support services in VA and the community”. This initiative represents an important effort by VA to promote collaboration with a broad range of community organizations as equal partners in the service of veteran needs. The purpose of the study is an initial assessment of the VCP program. Focus group interviews conducted in six sites in 2015 included 53 representatives of the local VA and community organizations involved with rural and urban VCPs across the US. Interview topics included the experiences and practices of VCP members, perceived benefits and challenges, and the characteristics and dynamics of rural and urban areas served by VCPs. Using a community-oriented conceptual framework, the analyses address VCP processes and preliminary outcomes, including VCP goals and activities, and VCP members’ perceptions of their efforts, benefits, challenges, and achievements. The results indicate largely positive perceptions of the VCP initiative and its early outcomes by both community and VA participants. Benefits and challenges vary by rural-urban community context and include resource limitations and the potential for VA dominance of other VCP partners. Although all VCPs identified significant benefits and challenges, time and resource constraints and local organizational dynamics varied by rural and urban context. Significant investments in VCPs will be required to increase their impacts.

Researchers have identified several factors that influence the academic success of college students, including, for example, personality traits, high-school academic achievement, and social class before entering college. In this case study, we contribute to this growing body of literature by analyzing the influence of sense of community (SOC) on student success, measured by student expectations that they will successfully graduate from their university. After surveying a sample of students at a private college in Provo, UT, USA, we found a positive correlation between SOC and graduation expectations, although our results varied between class standings. While senior students had the lowest levels of SOC compared to freshmen, they also had the highest indication that they expect to graduate. Freshmen and junior students, on the other hand, had the highest SOC compared to senior students but the lowest indication that they expect to graduate. Due to the association between SOC and graduation expectations, we argue that universities can help first- and second-year students feel more confident that they will graduate through initiatives that strengthen their sense of community.

Background:In breast cancer (BC), radiotherapy (RT) is used adjuvantly to prevent recurrence and also in the palliative setting. Clinical signs of RT response are often not apparent for several weeks post-treatment and we currently lack tools to predict or monitor tumor response to RT early during treatment. The aim was to identify tumor-secreted biomarkers whose release reflects response to RT, which could be monitored during treatment in the blood or intratumorally by an implantable biosensor, currently under development within the Implantable Microsystems for Personalised Anti-Cancer Therapy (IMPACT) program. Methods: A series of experiments assessed the effect of different radiation doses (2-10Gy) on 3 human BC cell lines – MDA-MB-231 (ER-), MCF-7 (ER+) and HBL-100 (ER-) –, 1 canine breast cancer and 2 sheep lung cancer lines. Culture media was collected from each dose experiment at a range of post-radiation time-points (1-24 hours). Proteins were isolated from collected media for secretome mass spectrometry (MS) analysis. A subset of treatment/time conditions were repeated in the same BC cell lines and radioresistant (RR) derivatives from which RNA was extracted and analysed using Lexogen QuantSeq for whole-genome transcriptomics.In-lab candidate biomarker validation was carried out using immuhistochemistry (IHC), immunofluorescence (IF) and western blotting (WB) using validated antibodies. Levels of candidate biomarkers were also assessed in normal and untreated BC tissues using IHC. ELISA-based methods are currently under investigation for detection of the lead candidate biomarkers in the blood of large animal cancer models treated with RT. Results: Biomarker discovery using the MS data revealed 4 promising candidates: EIF3G, SEC24C, YBX3 and TK1. These are released from BC and animal cancer cells sensitive to radiation in a dose-dependent manner 24 hours after treatment. Analysis of the transcriptomic data showed an 8-fold higher expression of the genes encoding the 4 candidates in the radio-sensitive parental cell lines compared to the RR cell lines. IF and WB confirmed lower intracellular expression of the 4 proteins in RR cells compared to the parental lines. WB of collected culture media confirmed release of each of the 4 candidates 24 hours after a 2Gy dose of radiation in only the parental lines. GAPDH was not found in these media samples, demonstrating that protein release was not due to cell lysis. Conclusions: · We have identified 4 promising biomarkers which are released from cancer cells sensitive to RT and not released from RR derivatives. · All 4 candidates are released 24 hours after a 2Gy radiation dose, which fits with the current clinical dosing schedule where radiation is administered at 24 hour intervals. Ongoing work will elucidate if these biomarkers can be reliably detected in blood or intratumorally using implantable biosensors. · There are currently no validated predictive tools to monitor RT response during treatment. If successfully validated, these biomarkers could have a clinical role in personalising RT dosing schedules and durations for solid tumors in the neoadjuvant and palliative setting, thus optimising treatment and preventing the administration of ineffective RT and its associated side effects. Citation Format: Meehan J, Gray M, Turnbull AK, Martinez-Perez C, Bonello M, Ward C, Langdon SP, McLaughlin S, MacLennan M, Dixon JM, Wills J, Quinn N, Finich AJ, von Kriegsheim A, Cameron D, Kunkler IH, Murray A, Argyle D. Tumor-secreted predictive biomarkers of response to radiotherapy in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-24.

Ongoing clinical and research efforts seek to optimise the use of endocrine therapy in the treatment of breast cancer. Accurate biomarkers are needed that predict response for individual patients. The presence of the estrogen receptor (ER) as the direct (for tamoxifen and fulvestrant) or indirect (for aromatase inhibitors) target molecule for endocrine therapy remains the foremost biomarker and determinant of response. However, ER expression only poorly predicts outcome and further indicators of response or resistance are required. The development and application of molecular signature assays such as Oncotype Dx, Prosigna, Mammaprint and Endopredict have provided valuable information on prognosis and these are being used to support clinical decision making on whether endocrine therapy alone alongside surgery is sufficient for ER-positive early stage breast cancers or whether combination of endocrine with chemotherapy are also warranted. Ki67, the proliferation marker, has been widely used in the neo-adjuvant (pre-operative) setting to help predict response and long term outcome. Gene expression studies within the same setting have allowed monitoring of changes of potential predictive markers. These have identified frequent changes in estrogen-regulated and proliferation genes. Specific molecules such as mutant ER may also prove helpful biomarkers in predicting outcome and monitoring response to treatment.

This study uses the Rural Utah Community Study (RUCS) to explore how social sustainability shapes a community’s approach to environmental sustainability. The results indicate that respondents who feel attached to and are satisfied with their community had a more positive relationship with the natural environment than those who were dissatisfied with their communities. We also find evidence that social ties, measured by the number of people known by their first name in the community, positively influence perceptions of the environment, and that a significant link exists between environmental sustainability and a higher sense of community belonging.

Background:Clinicians are encouraged to use non-pharmacologic interventions first as part of the treatment of responsive behaviours due to mental health conditions. Music therapy is an example of such an intervention. In recent years, there has been an increased research focus on individualized music (IM) because it considers patient’s personal music preferences. However, the findings of whether IM listening is more beneficial than general music listening has been inconsistent.Objective:This study is to further compare the effects of IM and elevator (baseline) music listening on enjoyment behaviours of geriatric inpatients.Methods:Fifteen participants were recruited from a geriatric psychiatry unit in an acute tertiary mental health facility in British Columbia, Canada. Their mean age was 74 years and their mean MMSE was 18. Each participant attended two 30-minute music listening sessions. Each session included a 15-minute baseline music playlist and a 15-minute IM playlist. The sequence of the two playlists was counterbalanced for each participant across the two sessions. The IM playlists were created by interviewing each participant with a personalized music preference questionnaire. The baseline (elevator) playlist was simply consisted of instrumental, non-lyrical jazz and classical music and was the same for every participant. The enjoyment behaviors during the sessions for each participant were measured by the Enjoyment Behavioral Coding Scheme (EBCS), which was developed for this project based on previous literature and was shown to have a good inter rater reliability.Results:The average total scores of the EBCS across two sessions of IM and baseline music listening were calculated for each participant. Paired samples t-test was used to compare the scores. Though the mean total score of the EBCS for IM session was higher than that for the baseline session, the t-test showed the difference did not reach statistical significance.Conclusion:Participants appeared to enjoy both the IM and baseline music sessions equally.

Introduction: Lugano 2014 criteria are the current standard for response assessment in lymphoma and incorporate 18F fludeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) into standard staging of FDG-avid lymphomas (Cheson, et al. J Clin Oncol 2014); bi-dimensional tumor measurements of up to six CT target lesions are used for non-FDG avid lymphomas, and when PET is unavailable. The Response Evaluation Criteria in Lymphoma (RECIL), developed more recently, showed that uni-dimensional measurements of up to three target lesions could provide response assessment at a similar accuracy to the Lugano criteria (Younes, et al. Annals Oncol 2017). In the Phase III GOYA trial (NCT01287741), complete response (CR) status by RECIL criteria showed high concordance with Lugano criteria and was highly prognostic for survival outcome in previously untreated patients (pts) with CD20-positive diffuse large B-cell lymphoma treated with obinutuzumab (G) plus chemotherapy (G-chemo) or rituximab (R)-chemo. Here, we compared the prognostic and predictive performance of the Lugano and RECIL criteria in pts from the Phase III GALLIUM trial (NCT01332968). Methods: Pts were randomized 1:1 to receive G or R plus CHOP, CVP, or bendamustine (stratification factors: chemotherapy regimen, Follicular Lymphoma International Prognostic Index and geographic region). FDG-PET scans were mandatory in the first 170 pts where a PET scanner was available, and optional thereafter, and were performed at screening and end of induction (EOI). Response was assessed by the investigator (INV) and an independent review committee (IRC) using Cheson 2007 criteria, the IRC also assessed EOI response using Lugano 2014 criteria. Response and progression-free survival (PFS) by RECIL 2017 criteria were retrospectively evaluated via a programming algorithm based on IRC-assessed 5PS scores and the individual lesion measurements from INV assessment. Response categories at EOI by RECIL criteria were cross-tabulated against those by Lugano criteria. Estimates of the treatment effect for PFS were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) using stratified log-rank tests. Landmark analyses of PFS and overall survival (OS) from EOI, by EOI CR/non-CR status were performed. The impact of covariates on the prognostic value for PFS and OS were analyzed using multivariable Cox models. Results: In GALLIUM, 1202 pts with follicular lymphoma (FL) were enrolled (601 per treatment arm), of which 595 had PET evaluable data (R-chemo, n=298; G-chemo, n=297). High concordance between Lugano and RECIL criteria for EOI CR was observed regardless of antibody received, with 416 pts classified as CR by RECIL among the 450 pts achieving complete metabolic response (CMR) by Lugano (416/450 [92.4%]; R-chemo, 199/216 [92.1%]; G-chemo, 217/234 [92.7%]) (Table). However, poor concordance was seen for progressive disease (PD), with 18/21 (85.7%) pts with progressive metabolic disease by Lugano classified as partial/minimal responders by RECIL. A strong correlation was observed between Cheson 2007 and RECIL PFS definitions, with a kappa estimate of 0.63 (95% CI: 0.58-0.69). EOI CR status by RECIL showed prognostic value by Cox multivariable regression analysis adjusted for stratification factors for PFS and OS; this prognostic value was similar with Lugano criteria (Figure). PFS rate by treatment arm for pts with a CR/CMR was higher by RECIL versus Lugano for both R-chemo and G-chemo (PFS rate at 3 years from EOI: RECIL: 86.0% and 89.7%; Lugano: 76.4% and 85.0%, respectively); similar results were seen with OS. G-chemo was associated with improved RECIL-PFS (from randomization) compared with R-chemo (HR, 0.72; 95% CI: 0.57-0.91; p=0.0069), similar to the GALLIUM 5-year updated analysis results by Cheson 2007 (HR, 0.76; 95% CI: 0.62-0.92; p=0.0043) (Townsend, et al. ASCO 2020). Conclusions: RECIL 2017 criteria showed high concordance with Lugano 2014 criteria with EOI CR strongly prognostic for improved outcomes versus non-CR; however, a discordance was observed for PD. A similar treatment difference between arms for PFS was detected with RECIL and Cheson 2007 criteria. RECIL criteria (uni-dimensional assessment of up to three target lesions) may be a suitable alternative to Lugano criteria (bi-dimensional assessment of up to six target lesions) in pts with previously untreated advanced-stage FL. Disclosures Kostakoglu: F. Hoffmann-La Roche: Consultancy. Davies:Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Celegene, Roche, Kite Pharma, Celegene: Honoraria; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Herold:Helios Klinikum Erfurt: Current Employment; F. Hoffmann-La Roche: Research Funding. Hiddemann:F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Marcus:Gilead: Consultancy; F. Hoffmann-La Roche: Honoraria; Janssen: Honoraria, Speakers Bureau. Trotman:Celgene: Research Funding; F. Hoffmann-La Roche: Research Funding; BeiGene: Research Funding; Takeda: Research Funding; PCYC: Research Funding. Knapp:F. Hoffmann-La Roche: Current Employment. Mattiello:F. Hoffmann-La Roche: Current Employment. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Sahin:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Ward:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Younes:AstraZeneca: Current Employment; MSKCC: Ended employment in the past 24 months; Janssen, Curis, Merck, Bristol-Myers Squibb, Syndax Pharmaceuticals, F. Hoffmann-La Roche, Curis (Inst), Johnson & Johnson (Inst), Novartis (Inst): Research Funding; Janssen, AbbVie, Merck, Curis, Epizyme, F. Hoffmann-La Roche, Takeda, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Celgene, Incyte, Janssen Pharmaceuticals, Merck, Sanofi, Seattle Genetics, Takeda Millennium: Honoraria; BioPath, Xynomic, Epizyme, and F. Hoffmann-La Roche: Consultancy.

Carbonic anhydrase inhibitors (CAIs) of the sulfonamide, sulfamate and coumarin classes bearing the phenylureido tail found in the clinically used drug Sorafenib, a multikinase inhibitor actually used for the management of hepatocellular carcinomas, are reported. All compounds were assayed on human (h) CA isoforms I, II, VII and IX, involved in various pathologies. Among the sulfonamides, several compounds were selective for inhibiting hCA IX, with KI values in the low nanomolar ranges (i.e. 0.7–30.2 nM). We explored the binding modes of such compounds by means of X-ray crystallographic studies on isoform hCA I in adduct with one sulfonamide and a sulfamate inhibitor. Antiproliferative properties of some sulfamates on breast tumor cell lines were also investigated.

Previous studies focusing on the effects of the social aspects of community have often used the Sense of Community Index (SCI), despite other research showing that it is not a good-fit measure for its expected dimensions. Using a sample of students from Brigham Young University, we performed confirmatory factor analysis of the SCI to assess 1-factor, 4-factor, 1-factor revised, 3-factor revised, 1-factor revised, 4-factor revised, and 1-factor revised models. Our study resulted in mixed findings: models were neither a poor-fit nor a good fit. Although the 4-factor revised model was the best fit, it did not measure the intended dimensions well. Our analysis indicates that future research investigating sense of community should use measures other than the SCI.

The immense costs in both financial terms and preclinical research effort that occur in the development of anticancer drugs are unfortunately not matched by a substantial increase in improved clinical therapies due to the high rate of failure during clinical trials. This may be due to issues with toxicity or lack of clinical effectiveness when the drug is evaluated in patients. Currently, much cancer research is driven by the need to develop therapies that can exploit cancer cell adaptations to conditions in the tumor microenvironment such as acidosis and hypoxia, the requirement for more-specific, targeted treatments, or the exploitation of 'precision medicine' that can target known genomic changes in patient DNA. The high attrition rate for novel anticancer therapies suggests that the preclinical methods used in screening anticancer drugs need improvement. This chapter considers the advantages and disadvantages of 3D organotypic models in both cancer research and cancer drug screening, particularly in the areas of targeted drugs and the exploitation of genomic changes that can be used for therapeutic advantage in precision medicine.

The immense costs in both financial terms and pre-clinical research effort that occur in the development of anti-cancer drugs are unfortunately not matched by a substantial increase in improved clinical therapies due to the high rate of failure during clinical trials. This may be due to issues with toxicity, or lack of clinical ef-fectiveness when the drug is evaluated in patients. Currently, much cancer re-search is driven by the need to develop therapies that can exploit cancer cell ad-aptations to conditions in the tumor microenvironment such as acidosis and hy-poxia, the requirement for more-specific, targeted treatments, or the exploitation of ‘precision medicine’ that can target known genomic changes in patient DNA. The high attrition rate for novel anti-cancer therapies suggests that the pre-clinical methods used in screening anti-cancer drugs need improvement. This chapter considers the advantages and disadvantages of 3D organotypic models in both cancer research and cancer drug screening, particularly in the areas of targeted drugs and the exploitation of genomic changes that can be used for therapeutic advantage in precision medicine

To better understand social sustainability in the context of rapid boom growth and decline, we examine longitudinal social change in the modern boomtown of Colstrip, MT. Using a mixed-methods approach that includes two waves of a community survey&mdash, administered in 1996 and 2018, respectively&mdash, and focus groups conducted in 2018&ndash, 2019, we explore shifts in residents&rsquo, sense of community as well as their perceptions and attitudes about current challenges to their community&rsquo, s future and sustainability. We show that, despite surviving previous boom and bust periods related to changes in the coal industry, this community now faces a new reality that involves the closure of all local power plants. However, both survey responses and residents&rsquo, narratives indicate a strong sense of community and support for developing strategies that address challenges to the town&rsquo, s future. This exploratory case study helps to extend the literature by contributing to a greater understanding of the experiences of contemporary workers who individually migrated to a small, rural energy town but who now, as a community, face an uncertain future, and by illuminating the role of sense of community in both social and environmental sustainability efforts.

Real‐time monitoring of tumor microenvironment parameters using an implanted biosensor could provide valuable information on the dynamic nature of a tumor's biology and its response to treatment. However, following implantation biosensors may lose functionality due to biofouling caused by the foreign body response (FBR). This study developed a novel tumor xenograft model to evaluate the potential of six biomaterials (silicon dioxide, silicon nitride, Parylene‐C, Nafion, biocompatible EPOTEK epoxy resin, and platinum) to trigger a FBR when implanted into a solid tumor. Biomaterials were chosen based on their use in the construction of a novel biosensor, designed to measure spatial and temporal changes in intra‐tumoral O2, and pH. None of the biomaterials had any detrimental effect on tumor growth or body weight of the murine host. Immunohistochemistry showed no significant changes in tumor necrosis, hypoxic cell number, proliferation, apoptosis, immune cell infiltration, or collagen deposition. The absence of biofouling supports the use of these materials in biosensors; future investigations in preclinical cancer models are required, with a view to eventual applications in humans. To our knowledge this is the first documented investigation of the effects of modern biomaterials, used in the production of implantable sensors, on tumor tissue after implantation. © 2018 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals, Inc. J Biomed Mater Res Part B, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1620–1633, 2019.

Our objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials (ClinicalTrials.gov identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naive patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively. The model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS. As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed; for each unit increase in the (log) ratio of MRD- rates between arms, the log of the PFS hazard ratio decreased by -0.188 (95% confidence interval, -0.321 to -0.055; P = .008). External model validation on the REACH trial and sensitivity analyses confirm the robustness and applicability of the surrogacy model. Our surrogacy model supports use of PB-MRD as a primary end point in randomized clinical trials of chemoimmunotherapy in CLL. Additional CLL trial data are required to establish a more precise quantitative relationship between MRD and PFS, and to support general applicability of MRD surrogacy for PFS across diverse patient characteristics, treatment regimens, and different treatment mechanisms of action.