Rubin H. Flocks and Colloidal Gold Treatments for Prostate Cancer

In the early 1950s, Rubin H. Flocks of the University of Iowa began to treat prostate cancer patients with colloidal gold (Au198) therapy, evolving his technique over nearly 25 years in 1515 patients. We reviewed the long-term outcomes of Flocks' prostate cancer patients as compared to those patients treated by other methods at the University of Iowa before Flocks' chairmanship. We reviewed archived patient records, Flocks' published data, and long-term survival data from the Iowa Tumor Registry to determine short- and long-term outcomes of Flocks' work with colloidal gold. We also reviewed the literature of Flocks’ time to compare his outcomes against those of his contemporaries. The use of colloidal gold, either as primary or adjunctive therapy, provided short- and long-term survival benefit for the majority of Flocks' patients as compared to historical treatment options (p < 0.001). Flocks' use of colloidal gold for the treatment of locally advanced prostate cancer offered short- and long-term survival benefits compared to other contemporary treatments

Quantitative Trait Loci Associated with Foliar Trigonelline Accumulation in Glycine Max L

The objective of this study was to utilize a Glycine max RIL population to (1) evaluate foliar trigonelline (TRG) content in field-grown soybean, (2) determine the heritability of TRG accumulation, and (3) identify DNA markers linked to quantitative trait loci (QTLs) conditioning variation in TRG accumulation. Frequency distributions of 70 recombinant inbred lines showed statistically no significant departure from normality (P > .05) for TRG accumulation measured at pod development stage (R4). Six different molecular linkage groups (LGs) (B2, C2, D2, G, J, and K) were identified to be linked to QTLs for foliar TRG accumulation. Two unique microsatellite markers (SSR) on two different linkage groups identified QTL significantly associated with foliar TRG accumulation: a region on LG J (Satt285) (P = .0019, R(2) = 15.9%) and a second region on LG C2 (Satt079) (P = .0029, R(2) = 13.4%)

Genomics of Drug Sensitivity in Cancer (GDSC): a Resource for Therapeutic Biomarker Discovery in Cancer Cells

Alterations in cancer genomes strongly influence clinical responses to treatment and in many instances are potent biomarkers for response to drugs. The Genomics of Drug Sensitivity in Cancer (GDSC) database (www.cancerRxgene.org) is the largest public resource for information on drug sensitivity in cancer cells and molecular markers of drug response. Data are freely available without restriction. GDSC currently contains drug sensitivity data for almost 75 000 experiments, describing response to 138 anticancer drugs across almost 700 cancer cell lines. To identify molecular markers of drug response, cell line drug sensitivity data are integrated with large genomic datasets obtained from the Catalogue of Somatic Mutations in Cancer database, including information on somatic mutations in cancer genes, gene amplification and deletion, tissue type and transcriptional data. Analysis of GDSC data is through a web portal focused on identifying molecular biomarkers of drug sensitivity based on queries of specific anticancer drugs or cancer genes. Graphical representations of the data are used throughout with links to related resources and all datasets are fully downloadable. GDSC provides a unique resource incorporating large drug sensitivity and genomic datasets to facilitate the discovery of new therapeutic biomarkers for cancer therapies

Living in the hinterland: Survey and excavations at Lohari Ragho 2015–2017

Living in the hinterland: Survey and excavations at Lohari Ragho 2015–201

Time for curriculum reform: the case of mathematics

Mathematics education is rarely out of the policy spotlight in England. Over the last ten years, considerable attention has been given to improving 14-19 mathematics curriculum pathways. In this paper we consider some of the challenges of enacting curriculum change by drawing upon evidence from our evaluation of the Mathematics Pathways Project. From 2004-10 this project, which was directed by England’s Qualifications and Curriculum Authority, aimed to improve the engagement, attainment and participation rates of 14-19 year old learners of mathematics. Our particular focus is upon the temporal problems of piloting new curriculum and assessment and we draw on Lemke’s discussion of time-scales, heterochrony and the adiabatic principle to consider the interlocking and interference of various change processes

The Impact of Falls: A Qualitative Study of the Experiences of People Receiving Haemodialysis

The prevalence of falls is high in people receiving haemodialysis (HD). This study aimed to explore the experiences of people receiving HD who had fallen in the last six months. A qualitative study, informed by constructivist grounded theory, used semi-structured interviews in combination with falls diaries. Twenty-five adults (mean age of 69 ± 10 years, 13 female, 13 White British) receiving HD with a history of at least one fall in the last six months (median 3, IQR 2−4) participated. Data were organised within three themes: (a) participants’ perceptions of the cause of their fall(s): poor balance, weakness, and dizziness, exacerbated by environmental causes, (b) the consequences of the fall: injuries were disproportionate to the severity of the fall leading to loss of confidence, function and disruptions to HD, (c) reporting and coping with falls: most did not receive any specific care regarding falls. Those who attended falls services reported access barriers. In response, personal coping strategies included avoidance, vigilance, and resignation. These findings indicate that a greater focus on proactively identifying falls, comprehensive assessment, and timely access to appropriate falls prevention programmes is required to improve care and outcomes

A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds.

The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.This research was supported with funding from Cancer Research UK and from the European Union to the EUROCAN Network of Excellence (FP7; grant numnumber 260791). M.C. has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sk1odowska-Curie grant agreement no. 660060 and was supported by the Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. R.N.B. is supported by the Wellcome Trust PhD Programme in Mathematical Genomics and Medicine. S-J.S. is supported by the Wellcome Trust PhD Programme for Clinicians in Cambridge. A.Bruna, O.M.R., E.M., V.S., and C.C. are members of the EurOPDX Consortium. Weare very grateful for the generosity of all the patients that donated samples for implantation. We are also deeply indebted to all the staff (surgeons, pathologists, oncologists, theatre staff, and other ancillary personnel) at the Cambridge Breast Unit, Cambridge University Hospital NHS Foundation Trust, for facilitating the timely collection of samples. We thank the Cancer Research UK Cambridge Institute Genomics, Bioinformatics, Histopathology, Flow Cytometry, Biological Resource, and Bio-repository Core Facilities for support during the execution of this project.This is the final version of the article. It first appeared from Elsevier at http://dx.doi.org/10.1016/j.cell.2016.08.041

Multi-institutional analysis of sequential intravesical gemcitabine and mitomycin C chemotherapy for non–muscle invasive bladder cancer

OBJECTIVE: Apart from cystectomy, few treatment options exist for the management of bacillus Calmette-Guerin refractory non–muscle invasive bladder cancer (NMIBC). We report a multi-institutional experience with sequential intravesical combination chemotherapy using gemcitabine and mitomycin C (MMC) for NMIBC in the treatment of high-risk patients. METHODS: We performed a retrospective review of patients who received 6 weekly treatments with sequential intravesical gemcitabine (1 g) and MMC (40 mg) chemotherapy for NMIBC. Gemcitabine was administered first and retained for 90 minutes and then drained. MMC was then administered directly after and retained for an additional 90 minutes. Forty-seven patients received treatment from 3 academic tertiary referral centers between 2000 and 2010. RESULTS: Forty-seven patients (median age 70, range 32–85; 36 males, 11 females) who previously failed a median of 2 intravesical treatments were reviewed. Complete response, 1-year, and 2-year recurrence-free survival rates for all patients were 68%, 48%, and 38%, respectively. Median recurrence-free survival for all patients was 9 months (range 1–80). Fourteen of 47 patients (30%) remained free of recurrence with a median time to follow-up of 26 months (range 6–80 mo). Ten patients required cystectomy. CONCLUSION: Sequential intravesical combination chemotherapy using gemcitabine and MMC appears to be a useful treatment for patients with high-grade NMIBC as well as those with prior bacillus Calmette-Guerin failure. Further prospective studies are warranted

The Codevelopment of “My Kidneys & Me”: A Digital Self-management Program for People With Chronic Kidney Disease

Background: Health care self-management is important for people living with nondialysis chronic kidney disease (CKD). However, the few available resources are of variable quality. Objective: This work describes the systematic codevelopment of “My Kidneys & Me” (MK&M), a theory-driven and evidence-based digital self-management resource for people with nondialysis CKD, guided by an established process used for the successful development of the diabetes education program MyDESMOND (Diabetes Education and Self-Management for Ongoing and Newly Diagnosed, DESMOND). Methods: A multidisciplinary steering group comprising kidney health care professionals and researchers and specialists in the development of complex interventions and digital health provided expertise in the clinical and psychosocial aspects of CKD, self-management, digital health, and behavior change. A patient and public involvement group helped identify the needs and priorities of MK&M and co-design the resource. MK&M was developed in 2 sequential phases. Phase 1 involved the codevelopment process of the MK&M resource (content and materials), using Intervention Mapping (IM) as a framework. The first 4 IM steps guided the development process: needs assessment was conducted to describe the context of the intervention; intervention outcomes, performance objectives, and behavioral determinants were identified; theory- and evidence-based change methods and practical strategies to deliver change methods were selected; and program components were developed and refined. Phase 2 involved the adoption and adaptation of the existing MyDESMOND digital platform to suit the MK&M resource. Results: The needs assessment identified that individuals with CKD have multiple differing needs and that delivering a self-management program digitally would enable accessible, tailored, and interactive information and support. The intended outcomes of MK&M were to improve and maintain effective self-management behaviors, including physical activity and lifestyle, improve knowledge, promote self-care skills, increase self-efficacy, and enhance well-being. This was achieved through the provision of content and materials designed to increase CKD knowledge and patient activation, reduce health risks, manage symptoms, and improve physical function. Theories and behavior change techniques selected include Self-Management Framework, Capability, Opportunity, Motivation Behavior model components of Behaviour Change Wheel and taxonomy of behavior change techniques, Health Action Process Approach Model, Common Sense Model, and Social Cognitive Theory. The program components developed comprised educational and behavior change sessions, health trackers (eg, monitoring blood pressure, symptoms, and exercise), goal-setting features, and forums for social support. The MyDESMOND digital platform represented an ideal existing platform to host MK&M; thus, the MyDESMOND interface and features were adopted and adapted for MK&M. Conclusions: Applying the IM framework enabled the systematic application of theory, empirical evidence, and practical perspectives in the codevelopment of MK&M content and materials. Adopting and adapting a preexisting platform provided a cost- and time-efficient approach for developing our digital intervention. In the next stage of work, the efficacy of MK&M in increasing patient activation will be tested in a randomized controlled trial

Eradication of Metastatic Renal Cell Carcinoma after Adenovirus-Encoded TNF-Related Apoptosis-Inducing Ligand (TRAIL)/CpG Immunotherapy

Despite evidence that antitumor immunity can be protective against renal cell carcinoma (RCC), few patients respond objectively to immunotherapy and the disease is fatal once metastases develop. We asked to what extent combinatorial immunotherapy with Adenovirus-encoded murine TNF-related apoptosis-inducing ligand (Ad5mTRAIL) plus CpG oligonucleotide, given at the primary tumor site, would prove efficacious against metastatic murine RCC. To quantitate primary renal and metastatic tumor growth in mice, we developed a luciferase-expressing Renca cell line, and monitored tumor burdens via bioluminescent imaging. Orthotopic tumor challenge gave rise to aggressive primary tumors and lung metastases that were detectable by day 7. Intra-renal administration of Ad5mTRAIL+CpG on day 7 led to an influx of effector phenotype CD4 and CD8 T cells into the kidney by day 12 and regression of established primary renal tumors. Intra-renal immunotherapy also led to systemic immune responses characterized by splenomegaly, elevated serum IgG levels, increased CD4 and CD8 T cell infiltration into the lungs, and elimination of metastatic lung tumors. Tumor regression was primarily dependent upon CD8 T cells and resulted in prolonged survival of treated mice. Thus, local administration of Ad5mTRAIL+CpG at the primary tumor site can initiate CD8-dependent systemic immunity that is sufficient to cause regression of metastatic lung tumors. A similar approach may prove beneficial for patients with metastatic RCC