Simon Wilkinson

Inactivation of cell death is a major step in tumor development, and p53, a tumor suppressor frequently mutated in cancer, is a critical mediator of cell death. While a role for p53 in apoptosis is well established, direct links to other pathways controlling cell death are unknown. Here we describe DRAM (damage-regulated autophagy modulator), a p53 target gene encoding a lysosomal protein that induces macroautophagy, as an effector of p53-mediated death. We show that p53 induces autophagy in a DRAM-dependent manner and, while overexpression of DRAM alone causes minimal cell death, DRAM is essential for p53-mediated apoptosis. Moreover, analysis of DRAM in primary tumors revealed frequent decreased expression often accompanied by retention of wild-type p53. Collectively therefore, these studies not only report a stress-induced regulator of autophagy but also highlight the relationship of DRAM and autophagy to p53 function and damage-induced programmed cell death.

Mechanisms of selective autophagy of the ER, known as ER-phagy, require molecular delineation, particularly in vivo. It is unclear how these events control ER proteostasis and cellular health. Here, we identify cell-cycle progression gene 1 (CCPG1), an ER-resident protein with no known physiological role, as a non-canonical cargo receptor that directly binds to core autophagy proteins via an LIR motif to mammalian ATG8 proteins and, independently and via a discrete motif, to FIP200. These interactions facilitate ER-phagy. The CCPG1 gene is inducible by the unfolded protein response and thus directly links ER stress to ER-phagy. In vivo, CCPG1 protects against ER luminal protein aggregation and consequent unfolded protein response hyperactivation and tissue injury of the exocrine pancreas. Thus, via identification of this autophagy protein, we describe an unexpected molecular mechanism of ER-phagy and provide evidence that this may be physiologically relevant in ER luminal proteostasis.

Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations. In the case of starvation, a signaling cascade involving AMPK and histone deacetylase SIRT1 displaces chromatin-bound BRD4, instigating autophagy gene activation and cell survival. Importantly, this program is directed independently and also reciprocally to the growth-promoting properties of BRD4 and is potently repressed by BRD4-NUT, a driver of NUT midline carcinoma. These findings therefore identify a distinct and selective mechanism of autophagy regulation.

The endoplasmic reticulum (ER) is a key site for lipid biosynthesis and folding of nascent transmembrane and secretory proteins. These processes are maintained by careful homeostatic control of the environment within the ER lumen. Signalling sensors within the ER detect perturbations within the lumen (ER stress) and employ downstream signalling cascades that engage effector mechanisms to restore homeostasis. The most studied signalling mechanism that the ER employs is the unfolded protein response (UPR), which is known to increase a number of effector mechanisms, including autophagy. In this chapter, we will discuss the emerging role of autophagy as a UPR effector pathway. We will focus on the recently discovered selective autophagy pathway for ER, ER-phagy, with particular emphasis on the structure and function of known mammalian ER-phagy receptors, namely FAM134B, SEC62, RTN3 and CCPG1. Finally, we conclude with our view of where the future of this field can lead our understanding of the involvement of ER-phagy in ER homeostasis.

Cellular homoeostatic pathways such as macroautophagy (hereinafter autophagy) are regulated by basic mechanisms that are conserved throughout the eukaryotic kingdom. However, it remains poorly understood how these mechanisms further evolved in higher organisms. Here we describe a modification in the autophagy pathway in vertebrates, which promotes its activity in response to oxidative stress. We have identified two oxidation-sensitive cysteine residues in a prototypic autophagy receptor SQSTM1/p62, which allow activation of pro-survival autophagy in stress conditions. The Drosophila p62 homologue, Ref(2)P, lacks these oxidation-sensitive cysteine residues and their introduction into the protein increases protein turnover and stress resistance of flies, whereas perturbation of p62 oxidation in humans may result in age-related pathology. We propose that the redox-sensitivity of p62 may have evolved in vertebrates as a mechanism that allows activation of autophagy in response to oxidative stress to maintain cellular homoeostasis and increase cell survival.

The endoplasmic reticulum (ER) network has central roles in metabolism and cellular organization. The ER undergoes dynamic alterations in morphology, molecular composition and functional specification. Remodelling of the network under fluctuating conditions enables the continual performance of ER functions and minimizes stress. Recent data have revealed that selective autophagy‐mediated degradation of ER fragments, or ER‐phagy, fundamentally contributes to this remodelling. This review provides a perspective on established views of selective autophagy, comparing these with emerging mechanisms of ER‐phagy and related processes. The text discusses the impact of ER‐phagy on the function of the ER‐ and the cell, both in normal physiology and when dysregulated within disease settings. Finally, unanswered questions regarding the mechanisms and significance of ER‐phagy are highlighted.

The p53-inducible BH3-only protein PUMA is a key mediator of p53-dependent apoptosis, and PUMA has been shown to function by activating Bax and mitochondrial outer membrane permeabilization. In this study, we describe an ability of PUMA to induce autophagy that leads to the selective removal of mitochondria. This function of PUMA depends on Bax/Bak and can be reproduced by overexpression of Bax. The induction of autophagy coincides with cytochrome c release, and taken together the results suggest that PUMA functions through Bax to induce mitochondrial autophagy in response to mitochondrial perturbations. Surprisingly, inhibition of PUMA or Bax-induced autophagy dampens the apoptotic response, suggesting that under some circumstances the selective targeting of mitochondria for autophagy can enhance apoptosis.

It is clear that changes in autophagy and autophagy regulators occur during tumor development and that this can have profound effects in certain tumor settings. The fact that p53, a key tumor suppressor mutated in approximately 50% of human cancers, has now also been shown to induce autophagy, has placed autophagy center stage in the minds of those interested in the development and treatment of malignant disease. p53 is a transcription factor that responds to cellular stress and prevents the propagation of cells which may otherwise form a tumor. The recent discovery, therefore, of DRAM (damage-regulated autophagy modulator) as a new p53 target which modulates autophagy is a major step forward in understanding how p53 controls autophagy and how this relates to tumor suppression. DRAM is a lysosomal protein that is not only critical for the ability of p53 to induce autophagy, but also for p53's ability to induce programmed cell death--a facet of p53 considered central to its tumor-suppressive effects. The fact that DRAM is also inactivated in certain cancers underscores its importance and highlights the possibility that autophagy may have a more profound role in cancer than was first believed.

K-Ras dependent non-small cell lung cancer (NSCLC) cells are ‘addicted’ to basal autophagy that reprograms cellular metabolism in a lysosomal-sensitive manner. Here we demonstrate that the xenophagy-associated kinase TBK1 drives basal autophagy, consistent with its known requirement in K-Ras-dependent NSCLC proliferation. Furthermore, basal autophagy in this context is characterised by sequestration of the xenophagy cargo receptor Ndp52 and its paralogue Tax1bp1, which we demonstrate here to be a bona fide cargo receptor. Autophagy of these cargo receptors promotes non-canonical NF-κB signalling. We propose that this TBK1-dependent mechanism for NF-κB signalling contributes to autophagy addiction in K-Ras driven NSCLC.

The endoplasmic reticulum (ER) is a fundamental organelle in cellular metabolism and signal transduction. It is subject to complex, dynamic sculpting of morphology and composition. Degradation of ER content has an important role to play here. Indeed, a major emerging player in ER turnover is ER-phagy, the degradation of ER fragments by selective autophagy, particularly macroautophagy. This article proposes a number of unifying principles of ER-phagy mechanism and compares these with other selective autophagy pathways. A perspective on the likely roles of ER-phagy in determining cell fate is provided. Emerging related forms of intracellular catabolism of the ER or contents, including ER-phagy by microautophagy and selective ER protein removal via the lysosome, are outlined for comparison. Unresolved questions regarding the mechanism of ER-phagy and its significance in cellular and organismal health are put forward. This review concludes with a perspective on how this fundamental knowledge might inform future clinical developments.

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant condition caused by mutations in the FLCN gene and characterized by benign hair follicle tumors, pneumothorax, and renal cancer. Folliculin (FLCN), the protein product of the FLCN gene, is a poorly characterized tumor suppressor protein, currently linked to multiple cellular pathways. Autophagy maintains cellular homeostasis by removing damaged organelles and macromolecules. Although the autophagy kinase ULK1 drives autophagy, the underlying mechanisms are still being unraveled and few ULK1 substrates have been identified to date. Here, we identify that loss of FLCN moderately impairs basal autophagic flux, while re-expression of FLCN rescues autophagy. We reveal that the FLCN complex is regulated by ULK1 and elucidate 3 novel phosphorylation sites (Ser406, Ser537, and Ser542) within FLCN, which are induced by ULK1 overexpression. In addition, our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). The FLCN-GABARAP association is modulated by the presence of either folliculin-interacting protein (FNIP)-1 or FNIP2 and further regulated by ULK1. As observed by elevation of GABARAP, sequestome 1 (SQSTM1) and microtubule-associated protein 1 light chain 3 (MAP1LC3B) in chromophobe and clear cell tumors from a BHD patient, we found that autophagy is impaired in BHD-associated renal tumors. Consequently, this work reveals a novel facet of autophagy regulation by ULK1 and substantially contributes to our understanding of FLCN function by linking it directly to autophagy through GABARAP and ULK1.

No AccessJournal of UrologyCLINICAL UROLOGY: Original Articles1 Dec 2002Attitudes and Use of Complementary Medicine in Men with Prostate Cancer SIMON WILKINSON, LEONARD G. GOMELLA, JOSEPH A. SMITH, MICHAEL K. BRAWER, NANCY A. DAWSON, ZEV WAJSMAN, LANTING DAI, and GERALD W. CHODAK SIMON WILKINSONSIMON WILKINSON More articles by this author , LEONARD G. GOMELLALEONARD G. GOMELLA More articles by this author , JOSEPH A. SMITHJOSEPH A. SMITH Financial interest and/or other relationship with Abbott, Anthra, Astra Zeneca, Glaxo, Pharmacia, Praecis Pharmaceutical, Inc. and TAP. More articles by this author , MICHAEL K. BRAWERMICHAEL K. BRAWER More articles by this author , NANCY A. DAWSONNANCY A. DAWSON More articles by this author , ZEV WAJSMANZEV WAJSMAN More articles by this author , LANTING DAILANTING DAI More articles by this author , and GERALD W. CHODAKGERALD W. CHODAK Financial interest and/or other relationship with Astra Zeneca. More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)64178-XAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Patients with cancer are increasingly incorporating complementary therapies into the overall treatment. We determine the prevalence and patterns of use of complementary therapies among patients with prostate cancer. Materials and Methods: Patients attending 6 urology institutions for prostate cancer management completed a self-administered questionnaire on complementary therapy. All men diagnosed with prostate cancer were eligible, regardless of age, stage of disease or treatment. Results: A total of 1,099 patients returned the questionnaire. The overall response rate was 78.5%. Complementary therapies had previously been or were currently being used by 23.5% (258) and 18.2% (200) of patients, respectively. Higher levels of education and income were associated with greater use of complementary therapy (p <0.002 by logistic regression). Patients with progressive disease or those primarily treated with hormones were most likely to use complementary therapy. Among the patients using complementary therapy 90% believed that it would help them live longer and improve quality of life, 60% believed it would relieve symptoms and 47% expected it to cure disease. Conclusions: Complementary therapies are used by a large number of patients with prostate cancer, particularly those with progressive disease or who have undergone multiple treatments. Health care providers need to recognize this growing pattern of use of complementary therapy. Among patients who use complementary therapy the perception of benefit is much greater than that supported by scientific data. Future research should aim to unravel the complex psychosocial dynamics that influence the decision to use complementary therapy by men with prostate cancer and to educate patients about the efficacy of such therapies. References 1 : The prevalence of complementary/alternative medicine in cancer: a systematic review. Cancer1998; 83: 777. Crossref, Medline, Google Scholar 2 : Informed Decisions. The Complete Book of Cancer Diagnosis, Treatment and Recovery. New York: Viking Press1997. Google Scholar 3 : Unconventional medicine in the United States. Prevalence, costs, and patterns of use. N Engl J Med1993; 328: 246. Crossref, Medline, Google Scholar 4 : Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr1999; 69: 842. Crossref, Medline, Google Scholar 5 : Adverse health effects of selenium in humans. Rev Environ Health2001; 16: 233. Crossref, Medline, Google Scholar 6 : Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol2000; 18: 3595. Crossref, Medline, Google Scholar 7 : Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA1998; 280: 1569. Crossref, Medline, Google Scholar 8 : A prospective study of dietary fat and risk of prostate cancer. J Natl Cancer Inst1993; 85: 1571. Crossref, Medline, Google Scholar 9 : Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States). Cancer Causes Control1998; 9: 553. Crossref, Medline, Google Scholar 10 : Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res1999; 59: 1225. Medline, Google Scholar 11 : Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol1998; 81: 730. Crossref, Medline, Google Scholar 12 : Vitamin and mineral supplement use is associated with reduced risk of prostate cancer. Cancer Epidemiol Biomarkers Prev1999; 8: 887. Medline, Google Scholar 13 : Alternative medicine use in patients with localized prostate carcinoma treated with curative intent. Cancer1999; 86: 2642. Crossref, Medline, Google Scholar 14 : Prevalence and patterns of the use of complementary therapies among prostate cancer patients: an epidemiological analysis. J Urol1999; 161: 1521. Link, Google Scholar 15 : Use of complementary health practices by prostate carcinoma patients undergoing radiation therapy. Cancer2000; 88: 615. Crossref, Medline, Google Scholar 16 : Use of alternative medicine by women with early-stage breast cancer. N Engl J Med1999; 340: 1733. Crossref, Medline, Google Scholar 17 : Enrollment begins for the largest-ever prostate cancer prevention trial. J Natl Cancer Inst2001; 93: 1132. Crossref, Medline, Google Scholar From the Department of Health Studies and Weiss Memorial Hospital, University of Chicago, Chicago, Illinois, the Department of Urology, Jefferson Medical College, Philadelphia, Pennsylvania, the Department of Urology, Vanderbilt University Medical Center, Nashville, Tennessee, Northwest Prostate Institute, Northwest Hospital, Seattle, Washington, Greenbaum Cancer Center, University of Maryland Medicine, Baltimore, Maryland and the Department of Urology, Florida University Medical College, Gainesville, Florida© 2002 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited byZuniga K, Zhao S, Kenfield S, Cedars B, Cowan J, Van Blarigan E, Broering J, Carroll P and Chan J (2019) Trends in Complementary and Alternative Medicine Use among Patients with Prostate CancerJournal of Urology, VOL. 202, NO. 4, (689-695), Online publication date: 1-Oct-2019. Cant S and Watts P (2018) Hidden in Plain Sight: Exploring Men’s Use of Complementary and Alternative MedicineThe Journal of Men’s Studies, 10.1177/1060826518778839, VOL. 27, NO. 1, (45-65), Online publication date: 1-Mar-2019. Chang A, Schwertschkow A, Greenlee H, Larkey L, Bloom-Foster J and Mehl-Madrona L (2019) Cancer Alternative Medicine and Cancer Prevention Research Fundamentals of Cancer Prevention, 10.1007/978-3-030-15935-1_9, (269-331), . Zaorsky N, Churilla T, Ruth K, Hayes S, Sobczak M, Hallman M, Smaldone M, Chen D and Horwitz E (2016) Men’s health supplement use and outcomes in men receiving definitive intensity-modulated radiation therapy for localized prostate cancerThe American Journal of Clinical Nutrition, 10.3945/ajcn.115.119958, VOL. 104, NO. 6, (1583-1593), Online publication date: 1-Dec-2016. Ng J, Liang L and Gagliardi A (2016) The quantity and quality of complementary and alternative medicine clinical practice guidelines on herbal medicines, acupuncture and spinal manipulation: systematic review and assessment using AGREE IIBMC Complementary and Alternative Medicine, 10.1186/s12906-016-1410-8, VOL. 16, NO. 1, Online publication date: 1-Dec-2016. Griebling T (2015) Re: Use of Herbal Medicines by Elderly Patients: A Systematic ReviewJournal of Urology, VOL. 193, NO. 4, (1290-1291), Online publication date: 1-Apr-2015. Bundon A and Hurd Clarke L (2012) ‘Keeping us from breaking’: elite athletes' access to and use of complementary and alternative medicineQualitative Research in Sport, Exercise and Health, 10.1080/2159676X.2012.712986, VOL. 6, NO. 1, (121-138), Online publication date: 2-Jan-2014. Kristoffersen A, Norheim A and Fønnebø V (2013) Complementary and Alternative Medicine Use among Norwegian Cancer Survivors: Gender-Specific Prevalence and Associations for UseEvidence-Based Complementary and Alternative Medicine, 10.1155/2013/318781, VOL. 2013, (1-10), . Horneber M, Bueschel G, Dennert G, Less D, Ritter E and Zwahlen M (2011) How Many Cancer Patients Use Complementary and Alternative MedicineIntegrative Cancer Therapies, 10.1177/1534735411423920, VOL. 11, NO. 3, (187-203), Online publication date: 1-Sep-2012. Ramsey S, Zeliadt S, Blough D, Fedorenko C, Fairweather M, McDermott C, Penson D, Van Den Eeden S, Hamilton A and Arora N (2012) Complementary and Alternative Medicine Use, Patient-reported Outcomes, and Treatment Satisfaction Among Men With Localized Prostate CancerUrology, 10.1016/j.urology.2012.01.023, VOL. 79, NO. 5, (1034-1041), Online publication date: 1-May-2012. Choi J, Chang Y, Hong Y, Heo D, Kim S, Lee J, Choi J, Kang K, Kim S, Jeong H, Lee C, Choi Y, Lim H and Yun Y (2012) Complementary and Alternative Medicine Use among Cancer Patients at the End of Life: Korean National StudyAsian Pacific Journal of Cancer Prevention, 10.7314/APJCP.2012.13.4.1419, VOL. 13, NO. 4, (1419-1424), Online publication date: 30-Apr-2012. Bauer-Wu S and Decker G (2012) Integrative Oncology Imperative for NursesSeminars in Oncology Nursing, 10.1016/j.soncn.2011.11.002, VOL. 28, NO. 1, (2-9), Online publication date: 1-Feb-2012. Fønnebø V, Grimsgaard S, Walach H, Ritenbaugh C, Norheim A, Macpherson H, Lewith G, Launsø L, Koithan M, Falkenberg T, Boon H and Aickin M (2012) Researching complementary and alternative treatments: The gatekeepers are not at home Traditional, Complementary and Integrative Medicine, 10.1007/978-1-137-26559-3_23, (196-203), . Lin Y, Chen K and Chiu J (2017) Trends in Chinese Medicine Use Among Prostate Cancer Patients Under National Health Insurance in TaiwanIntegrative Cancer Therapies, 10.1177/1534735410392576, VOL. 10, NO. 4, (317-327), Online publication date: 1-Dec-2011. Butler S, Owen-Smith A, DiIorio C, Goodman M, Liff J and Steenland K (2011) Use of Complementary and Alternative Medicine Among Men with Prostate Cancer in a Rural SettingJournal of Community Health, 10.1007/s10900-011-9402-6, VOL. 36, NO. 6, (1004-1010), Online publication date: 1-Dec-2011. Ernst E and Hung S (2011) Great ExpectationsThe Patient: Patient-Centered Outcomes Research, 10.2165/11586490-000000000-00000, VOL. 4, NO. 2, (89-101), Online publication date: 1-Jun-2011. Helpman L, Ferguson S, Mackean M, Rana A, Le L, Atkinson M, Rogerson A and Mackay H (2011) Complementary and Alternative Medicine Use Among Women Receiving Chemotherapy for Ovarian Cancer in 2 Patient PopulationsInternational Journal of Gynecologic Cancer, 10.1097/IGC.0b013e31820fa24a, VOL. 21, NO. 3, (587-593), Online publication date: 1-Apr-2011. Westerlund A, Steineck G, Bälter K, Stattin P, Grönberg H and Hedelin M (2011) Dietary supplement use patterns in men with prostate cancer: the Cancer Prostate Sweden StudyAnnals of Oncology, 10.1093/annonc/mdq456, VOL. 22, NO. 4, (967-972), Online publication date: 1-Apr-2011. Bishop F, Rea A, Lewith H, Chan Y, Saville J, Prescott P, Elm E and Lewith G (2010) Complementary medicine use by men with prostate cancer: a systematic review of prevalence studiesProstate Cancer and Prostatic Diseases, 10.1038/pcan.2010.38, VOL. 14, NO. 1, (1-13), Online publication date: 1-Mar-2011. Beard C, Stason W, Wang Q, Manola J, Dean-Clower E, Dusek J, DeCristofaro S, Webster A, Doherty-Gilman A, Rosenthal D and Benson H (2010) Effects of complementary therapies on clinical outcomes in patients being treated with radiation therapy for prostate cancerCancer, 10.1002/cncr.25291, VOL. 117, NO. 1, (96-102), Online publication date: 1-Jan-2011. Lin Y, Chen K and Chiu J (2010) Prevalence, Patterns, and Costs of Chinese Medicine Use Among Prostate Cancer Patients: A Population-Based Study in TaiwanIntegrative Cancer Therapies, 10.1177/1534735409359073, VOL. 9, NO. 1, (16-23), Online publication date: 1-Mar-2010. Yoshimura K, Sumiyoshi Y, Kamoto T, Ogawa O, Arai Y, Kakehi Y, Terai A, Kanamaru H, Kawakita M and Kinukawa N (2010) Transition Behavior in the Use of Complementary and Alternative Medicine during Follow-up after Radical Prostatectomy: A Multicenter Survey in JapanHealth, 10.4236/health.2010.212217, VOL. 02, NO. 12, (1460-1465), . Haseen F, Cantwell M, O'Sullivan J and Murray L (2009) Is there a benefit from lycopene supplementation in men with prostate cancer? A systematic reviewProstate Cancer and Prostatic Diseases, 10.1038/pcan.2009.38, VOL. 12, NO. 4, (325-332), Online publication date: 1-Dec-2009. Habermann T, Thompson C, LaPlant B, Bauer B, Janney C, Clark M, Rummans T, Maurer M, Sloan J, Geyer S and Cerhan J (2009) Complementary and alternative medicine use among long-term lymphoma survivors: A pilot studyAmerican Journal of Hematology, 10.1002/ajh.21554, VOL. 84, NO. 12, (795-798), Online publication date: 1-Dec-2009. Cassileth B, Gubili J and Simon Yeung K (2009) Integrative medicine: complementary therapies and supplementsNature Reviews Urology, 10.1038/nrurol.2009.41, VOL. 6, NO. 4, (228-233), Online publication date: 1-Apr-2009. Haseen F, Cantwell M, O'Sullivan J and Murray L (2009) Is there a benefit from lycopene supplementation in men with prostate cancer? A systematic reviewProceedings of the Nutrition Society, 10.1017/S0029665109990802, VOL. 68, NO. OCE3, . Porter M, Kolva E, Ahl R and Diefenbach M (2008) Changing patterns of CAM use among prostate cancer patients two years after diagnosis: Reasons for maintenance or discontinuationComplementary Therapies in Medicine, 10.1016/j.ctim.2008.04.001, VOL. 16, NO. 6, (318-324), Online publication date: 1-Dec-2008. Shafi G, Noorul Ha T and Ahmed Syed N (2008) Methanolic Extract of Nigella sativa Seeds is Potent Clonogenic Inhibitor of PC3 CellsInternational Journal of Pharmacology, 10.3923/ijp.2008.477.481, VOL. 4, NO. 6, (477-481), Online publication date: 15-Oct-2008. WILKINSON S, FARRELLY S, LOW J, CHAKRABORTY A, WILLIAMS R and WILKINSON S (2008) The use of complementary therapy by men with prostate cancer in the UKEuropean Journal of Cancer Care, 10.1111/j.1365-2354.2007.00904.x, VOL. 17, NO. 5, (492-499), Online publication date: 1-Sep-2008. Parsons J, Newman V, Mohler J, Pierce J, Paskett E and Marshall J (2008) The Men's Eating and Living (MEAL) Study: A Cancer and Leukemia Group B Pilot Trial of Dietary Intervention for the Treatment of Prostate CancerUrology, 10.1016/j.urology.2007.11.050, VOL. 72, NO. 3, (633-637), Online publication date: 1-Sep-2008. Parsons J, Newman V, Mohler J, Pierce J, Flatt S and Marshall J (2008) Dietary modification in patients with prostate cancer on active surveillance: a randomized, multicentre feasibility studyBJU International, 10.1111/j.1464-410X.2007.07365.x, VOL. 101, NO. 10, (1227-1231), Online publication date: 1-May-2008. Spadacio C and Barros N (2008) Uso de medicinas alternativas e complementares por pacientes com câncer: revisão sistemáticaRevista de Saúde Pública, 10.1590/S0034-89102008000100023, VOL. 42, NO. 1, (158-164), Online publication date: 1-Feb-2008. Velicer C and Ulrich C (2008) Vitamin and Mineral Supplement Use Among US Adults After Cancer Diagnosis: A Systematic ReviewJournal of Clinical Oncology, 10.1200/JCO.2007.13.5905, VOL. 26, NO. 4, (665-673), Online publication date: 1-Feb-2008. Janssen T (2008) Counselling of the Prostate Cancer Patient as a Whole PersonEuropean Urology Supplements, 10.1016/j.eursup.2007.10.002, VOL. 7, NO. 1, (29-34), Online publication date: 1-Feb-2008. Schulman C and Montorsi F (2008) Multidisciplinary Management of the Prostate Cancer Patient: Introduction and ConclusionsEuropean Urology Supplements, 10.1016/j.eursup.2007.10.001, VOL. 7, NO. 1, (1-5), Online publication date: 1-Feb-2008. White M, Verhoef M, Davison B, Gunn H and Cooke K (2008) Seeking Mind, Body and Spirit Healing–-Why Some Men with Prostate Cancer Choose CAM (Complementary and Alternative Medicine) over Conventional Cancer TreatmentsIntegrative Medicine Insights, 10.4137/IMI.S377, VOL. 3, (IMI.S377), Online publication date: 1-Jan-2008. Fønnebø V, Grimsgaard S, Walach H, Ritenbaugh C, Norheim A, MacPherson H, Lewith G, Launsø L, Koithan M, Falkenberg T, Boon H and Aickin M (2007) Researching complementary and alternative treatments – the gatekeepers are not at homeBMC Medical Research Methodology, 10.1186/1471-2288-7-7, VOL. 7, NO. 1, Online publication date: 1-Dec-2007. Eschiti V (2016) Lesson From Comparison of CAM Use by Women With Female-Specific Cancers to Others: It's Time to Focus on Interaction Risks With CAM TherapiesIntegrative Cancer Therapies, 10.1177/1534735407309257, VOL. 6, NO. 4, (313-344), Online publication date: 1-Dec-2007. EVANS M, SHAW A, SHARP D, THOMPSON E, FALK S, TURTON P and THOMPSON T (2007) Men with cancer: is their use of complementary and alternative medicine a response to needs unmet by conventional care?European Journal of Cancer Care, 10.1111/j.1365-2354.2007.00786.x, VOL. 16, NO. 6, (517-525), Online publication date: 1-Nov-2007. Rice L, Handayani R, Cui Y, Medrano T, Samedi V, Baker H, Szabo N, Rosser C, Goodison S and Shiverick K (2007) Soy Isoflavones Exert Differential Effects on Androgen Responsive Genes in LNCaP Human Prostate Cancer CellsThe Journal of Nutrition, 10.1093/jn/137.4.964, VOL. 137, NO. 4, (964-972), Online publication date: 1-Apr-2007. Barber N, Zhang X, Zhu G, Pramanik R, Barber J, Martin F, Morris J and Muir G (2006) Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical studyProstate Cancer and Prostatic Diseases, 10.1038/sj.pcan.4500895, VOL. 9, NO. 4, (407-413), Online publication date: 1-Dec-2006. Zeliadt S, Ramsey S, Penson D, Hall I, Ekwueme D, Stroud L and Lee J (2006) Why do men choose one treatment over another?Cancer, 10.1002/cncr.21822, VOL. 106, NO. 9, (1865-1874), Online publication date: 1-May-2006. Maccagnano C, Salonia A, Briganti A, Teillac P, Schulman C, Montorsi F and Rigatti P (2006) A Critical Analysis of Permixon™ in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic EnlargementEuropean Urology Supplements, 10.1016/j.eursup.2006.02.006, VOL. 5, NO. 4, (430-440), Online publication date: 1-Apr-2006. Krasuski R, Michaelis K and Eckart R (2006) The cardiovascular patient's perceptions of complementary and alternative medicineClinical Cardiology, 10.1002/clc.4960290407, VOL. 29, NO. 4, (161-164), Online publication date: 1-Apr-2006. Santillo V and Lowe F (2006) Role of vitamins, minerals and supplements in the prevention and management of prostate cancerInternational braz j urol, 10.1590/S1677-55382006000100002, VOL. 32, NO. 1, (3-14), Online publication date: 1-Feb-2006. Chong O (2006) An Integrative Approach to Addressing Clinical Issues in Complementary and Alternative Medicine in an Outpatient Oncology CenterClinical Journal of Oncology Nursing, 10.1188/06.CJON.83-88, VOL. 10, NO. 1, (83-88), Online publication date: 1-Feb-2006. Kim C, Park S, Lee S, Lee J, Chung H, Chung M, Yoon D, Cheon J, Kim W, Chung B, Hong S, Song J, Chang S, Choi H, Rim J, Cho Y, Moon K and Kim B (2006) The Use of Complementary and Alternative Medicine in Patients with a Urological MalignancyKorean Journal of Urology, 10.4111/kju.2006.47.6.620, VOL. 47, NO. 6, (620), . Verhoef M, Balneaves L, Boon H and Vroegindewey A (2016) Reasons for and Characteristics Associated With Complementary and Alternative Medicine Use Among Adult Cancer Patients: A Systematic ReviewIntegrative Cancer Therapies, 10.1177/1534735405282361, VOL. 4, NO. 4, (274-286), Online publication date: 1-Dec-2005. Hann D, Baker F, Roberts C, Witt C, McDonald J, Livingston M, Ruiterman J, Ampela R, Crammer C and Kaw O (2016) Use of Complementary Therapies Among Breast and Prostate Cancer Patients During Treatment: A Multisite StudyIntegrative Cancer Therapies, 10.1177/1534735405282109, VOL. 4, NO. 4, (294-300), Online publication date: 1-Dec-2005. Chan J, Elkin E, Silva S, Broering J, Latini D and Carroll P (2005) Total and specific complementary and alternative medicine use in a large cohort of men with prostate cancerUrology, 10.1016/j.urology.2005.06.003, VOL. 66, NO. 6, (1223-1228), Online publication date: 1-Dec-2005. Molassiotis A, Fernandez-Ortega P, Pud D, Ozden G, Platin N, Hummerston S, Scott J, Panteli V, Gudmundsdottir G, Selvekerova S, Patiraki E and Kearney N (2005) Complementary and alternative medicine use in colorectal cancer patients in seven European countriesComplementary Therapies in Medicine, 10.1016/j.ctim.2005.07.002, VOL. 13, NO. 4, (251-257), Online publication date: 1-Dec-2005. Roberts C, Baker F, Hann D, Runfola J, Witt C, McDonald J, Livingston M, Ruiterman J, Ampela R, Kaw O and Blanchard C (2008) Patient-Physician Communication Regarding Use of Complementary Therapies During Cancer TreatmentJournal of Psychosocial Oncology, 10.1300/J077v23n04_03, VOL. 23, NO. 4, (35-60), Online publication date: 1-Sep-2005. Isikhan V, Komurcu S, Ozet A, Arpaci F, Ozturk B, Balbay O and Guner P (2005) The Status of Alternative Treatment in Cancer Patients in TurkeyCancer Nursing, 10.1097/00002820-200509000-00004, VOL. 28, NO. 5, (355-362), Online publication date: 1-Sep-2005. Yoshimura K, Ueda N, Ichioka K, Matsui Y, Terai A and Arai Y (2005) Use of complementary and alternative medicine by patients with urologic cancer: a prospective study at a single Japanese institutionSupportive Care in Cancer, 10.1007/s00520-005-0842-3, VOL. 13, NO. 9, (685-690), Online publication date: 1-Sep-2005. Lee H, Schmidt K and Ernst E (2012) Acupuncture for the relief of cancer-related pain - a systematic reviewEuropean Journal of Pain, 10.1016/j.ejpain.2004.10.004, VOL. 9, NO. 4, (437-437), Online publication date: 1-Aug-2005. Wiygul J, Evans B, Peterson B, Polascik T, Walther P, Robertson C, Albala D and Demark-Wahnefried W (2005) Supplement use among men with prostate cancerUrology, 10.1016/j.urology.2005.01.035, VOL. 66, NO. 1, (161-166), Online publication date: 1-Jul-2005. Singh H, Maskarinec G and Shumay D (2016) Understanding the Motivation for Conventional and Complementary/Alternative Medicine Use Among Men With Prostate CancerIntegrative Cancer Therapies, 10.1177/1534735405276358, VOL. 4, NO. 2, (187-194), Online publication date: 1-Jun-2005. Spanner E and Duncan A (2005) Prevalence of dietary supplement use in adults with chronic renal insufficiencyJournal of Renal Nutrition, 10.1053/j.jrn.2005.01.005, VOL. 15, NO. 2, (204-210), Online publication date: 1-Apr-2005. White M and Verhoef M (2016) Toward a Patient-Centered Approach: Incorporating Principles of Participatory Action Research Into Clinical StudiesIntegrative Cancer Therapies, 10.1177/1534735404273727, VOL. 4, NO. 1, (21-24), Online publication date: 1-Mar-2005. Tas F, Ustuner Z, Can G, Eralp Y, Camlica H, Basaran M, Karagol H, Sakar B, Disci R and Topuz E (2009) The prevalence and determinants of the use of complementary and alternative medicine in adult Turkish cancer patientsActa Oncologica, 10.1080/02841860510007549, VOL. 44, NO. 2, (161-167), Online publication date: 1-Mar-2005. Chang E, Hedelin M, Adami H, Gronberg H and Balter K (2004) Re: Zinc Supplement Use and Risk of Prostate CancerJNCI Journal of the National Cancer Institute, 10.1093/jnci/djh206, VOL. 96, NO. 14, (1108-1108), Online publication date: 21-Jul-2004. Ranga R, Girija R, Nur-e-alam M, Sathishkumar S, Akbarsha M, Thirugnanam S, Rohr J, Ahmed M and Chendil D (2004) Rasagenthi lehyam (RL) a novel complementary and alternative medicine for prostate cancerCancer Chemotherapy and Pharmacology, 10.1007/s00280-004-0770-9, VOL. 54, NO. 1, (7-15), Online publication date: 1-Jul-2004. Flaherty J and Takahashi R (2004) The use of complementary and alternative medical therapies among older persons around the worldClinics in Geriatric Medicine, 10.1016/j.cger.2004.02.003, VOL. 20, NO. 2, (179-200), Online publication date: 1-May-2004. Chendil D, Ranga R, Meigooni D, Sathishkumar S and Ahmed M (2004) Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3Oncogene, 10.1038/sj.onc.1207284, VOL. 23, NO. 8, (1599-1607), Online publication date: 26-Feb-2004. Beebe-Dimmer J, Wood D, Gruber S, Douglas J, Bonner J, Mohai C, Zuhlke K, Shepherd C and Cooney K (2004) Use of complementary and alternative medicine in men with family history of prostate cancer: a pilot studyUrology, 10.1016/j.urology.2003.09.036, VOL. 63, NO. 2, (282-287), Online publication date: 1-Feb-2004. Leach M (2004) Public, nurse and medical practitioner attitude and practice of natural medicineComplementary Therapies in Nursing and Midwifery, 10.1016/S1353-6117(03)00082-9, VOL. 10, NO. 1, (13-21), Online publication date: 1-Feb-2004. Ernst E and Stevinson C Complementary and Alternative Medicine in Patients with Cancer Cancer, Culture, and Communication, 10.1007/0-306-48007-7_10, (221-237) Ernst E (2003) The current position of complementary/alternative medicine in cancerEuropean Journal of Cancer, 10.1016/S0959-8049(03)00604-X, VOL. 39, NO. 16, (2273-2277), Online publication date: 1-Nov-2003. Boon H, Westlake K, Stewart M, Gray R, Fleshner N, Gavin A, Brown J and Goel V (2003) Use of complementary/alternative medicine by men diagnosed with prostate cancer: prevalence and characteristicsUrology, 10.1016/S0090-4295(03)00668-X, VOL. 62, NO. 5, (849-853), Online publication date: 1-Nov-2003. Ernst E (2003) Complementary therapies for cancer, more good than harm?Wiener Klinische Wochenschrift, 10.1007/BF03040882, VOL. 115, NO. 19-20, (676-677), Online publication date: 1-Oct-2003. White M and Verhoef M (2016) Decision-Making Control: Why Men Decline Treatment for Prostate CancerIntegrative Cancer Therapies, 10.1177/1534735403256411, VOL. 2, NO. 3, (217-224), Online publication date: 1-Sep-2003. Eng J, Ramsum D, Verhoef M, Guns E, Davison J and Gallagher R (2016) A Population-Based Survey of Complementary and Alternative Medicine Use in Men Recently Diagnosed with Prostate CancerIntegrative Cancer Therapies, 10.1177/1534735403256207, VOL. 2, NO. 3, (212-216), Online publication date: 1-Sep-2003. (2010) Complementary Medicine — GeneralFocus on Alternative and Complementary Therapies, 10.1211/fact.2003.00234, VOL. 8, NO. 2, (253-253), Online publication date: 1-Jun-2003. Wilkinson S and Chodak G (2003) Critical Review of Complementary Therapies for Prostate CancerJournal of Clinical Oncology, 10.1200/JCO.2003.08.083, VOL. 21, NO. 11, (2199-2210), Online publication date: 1-Jun-2003. Shah J (2015) Dietary Factors for Prostate CancerUroOncology, 10.1080/15610950310001618157, VOL. 3, NO. 2, (43-49), Online publication date: 1-Jun-2003. Ponholzer A, Struhal G and Madersbacher S (2003) Frequent Use of Complementary Medicine by Prostate Cancer PatientsEuropean Urology, 10.1016/S0302-2838(03)00155-6, VOL. 43, NO. 6, (604-608), Online publication date: 1-Jun-2003. Barber N (2003) The tomato: an important part of the urologist's diet?BJU International, 10.1046/j.1464-410X.2003.04097.x, VOL. 91, NO. 4, (307-309), Online publication date: 1-Mar-2003. Volume 168Issue 6December 2002Page: 2505-2509 Advertisement Copyright & Permissions© 2002 by American Urological Association, Inc.Keywordscomplementary therapiesprostateneoplasmsMetricsAuthor Information SIMON WILKINSON More articles by this author LEONARD G. GOMELLA More articles by this author JOSEPH A. SMITH Financial interest and/or other relationship with Abbott, Anthra, Astra Zeneca, Glaxo, Pharmacia, Praecis Pharmaceutical, Inc. and TAP. More articles by this author MICHAEL K. BRAWER More articles by this author NANCY A. DAWSON More articles by this author ZEV WAJSMAN More articles by this author LANTING DAI More articles by this author GERALD W. CHODAK Financial interest and/or other relationship with Astra Zeneca. More articles by this author Expand All Advertisement PDF downloadLoading ...

The selective regulation of macroautophagy remains poorly defined. Here we report that PDGFR signaling is an essential selective promoter of hypoxia-induced macroautophagy. Hypoxia-induced macroautophagy in tumor cells is also HIF1alpha-dependent, with HIF1alpha integrating signals from PDGFRs and oxygen tension. Inhibition of PDGFR signaling reduces HIF1alpha half-life, despite buffering of steady-state protein levels by a compensatory increase in HIF1alpha mRNA. This markedly changes HIF1alpha protein pool dynamics, and consequently reduces the HIF1alpha transcriptome. As autocrine growth factor signaling is a hallmark of many cancers, cell-autonomous enhancement of HIF1alpha-mediated macroautophagy may represent a mechanism for augmenting tumor cell survival under hypoxic conditions.

To determine whether an education program on prostate cancer could improve awareness and knowledge among African-American men. African-American men have the world's highest incidence of prostate cancer and more than twice the mortality compared with white men. Screening programs for prostate cancer have not been successful in attracting African-American participation. One explanation is a poor awareness and knowledge about the disease among this high-risk population.We surveyed 900 African-American adults attending prostate cancer education seminars in community settings throughout Illinois between March 1998 and January 2001. Participants were asked to complete a multiple-choice questionnaire on topics related to prostate cancer. The main outcome measures were a change in awareness and knowledge of prostate cancer after the 1-hour educational seminar.The mean survey score improved from 26.0% before the seminar to 73.3% after it (P <0.0001). Every multiple-choice question was answered correctly more often after the seminar than before it. Increasing levels of education and income were associated with higher before and after scores (P <0.001). Men achieved a significantly greater score improvement (mean 48.1%) compared with women (mean 41.1%; P = 0.006). Previous screening for prostate cancer was reported by 23% of the participants. Using logistic regression analyses, higher levels of education and income correlated with higher rates of screening. After the seminar, 63.1% stated the intention to undergo screening.Our results demonstrate that prostate cancer awareness and knowledge can improve dramatically after a 1-hour seminar on the topic. Additional studies to evaluate the long-term retention of knowledge and impact on behavior are warranted.

Conventional imaging modalities, such as computerized tomography and magnetic resonance imaging, lack sensitivity and specificity for detecting recurrent prostate cancer after radical surgery. We evaluated the role of the indium-capromab pendetide scan, otherwise known as the ProstaScint (Cytogen Corp., Princeton, New Jersey) scan, in this setting.A retrospective review was performed of 42 patients undergoing ProstaScint imaging for biochemical progression after radical prostatectomy. Of these patients 16 (38.1%) subsequently completed a course of salvage radiation therapy.Median prostate specific antigen (PSA) immediately prior to ProstaScint imaging was 1.2 ng/ml (range 0.2 to 4.8). Abnormal accumulation on the ProstaScint scan was detected in 36 patients (85.7%). Of the 16 patients undergoing salvage radiation therapy 15 had uptake isolated to the prostatic fossa on ProstaScint imaging. Ten of these 15 patients (66.7%) achieved undetectable PSA after radiation therapy, while 5 (33.3%) had little or no response. Using American Society for Therapeutic Radiology and Oncology criteria 3 of 10 responders had relapse after an average of 9 months. The remaining 7 patients remained biochemically free of disease at last followup.ProstaScint imaging is capable of detecting recurrent prostate cancer at low PSA levels. However, only 7 of 15 men (46.7%) with ProstaScint uptake isolated to the prostatic fossa showed a durable response to salvage radiation therapy. Based on these findings patients might be better treated based on the rate of increase in PSA rather than on routine scanning with this test.

AbstractAutophagy is a membrane-trafficking process that serves to deliver cytoplasmic proteins and organelles to the lysosome for degradation. The process is genetically defined and many of the factors involved are conserved from yeast to man. Recently, a number of new autophagy regulators have been defined, including the Damage-Regulated Autophagy Modulator (DRAM), which is a lysosomal protein that links autophagy and the tumor suppressor, p53. We describe here analysis of DRAM-related proteins which reveals evolutionary conservation and divergence of DRAM’s role in autophagy. We report that humans have 5 other proteins that show significant homology to DRAM. The closest of these, which we have termed DRAM2, displays 45% identity and 67% conservation when compared to DRAM. Interestingly, although similar to DRAM in terms of homology, DRAM2 is different from DRAM as it not induced by p53 or p73. DRAM2 is also a lysosomal protein, but again unlike DRAM its over-expression does not modulate autophagy. In contrast to humans, the Drosophila genome only encodes one DRAM-like protein, which is approximately equal in similarity to human DRAM and DRAM2. This questions, therefore, whether DRAM function is conserved from fly to man or whether DRAM’s capacity to regulate autophagy has evolved in higher eukaryotes. Expression of DmDRAM, however, clearly revealed an ability to modulate autophagy. This points, therefore, to a conserved role of DRAM in this process and that additional human proteins have more recently evolved which, while potentially sharing some similarities to DRAM function, may not be as intrinsically connected to autophagy regulation.

We have recently described that autophagic targeting of Src maintains cancer cell viability when FAK signalling is defective. Here, we show that the Ret tyrosine kinase is also degraded by autophagy in cancer cells with altered/reduced FAK signalling, preventing its binding to FAK at integrin adhesions. Inhibition of autophagy restores Ret localization to focal adhesions. Importantly, Src kinase activity is required to target Ret to autophagosomes and enhance Ret degradation. Src is thus a general mediator of selective autophagic targeting of adhesion-linked kinases, and Ret a second FAK-binding tyrosine kinase degraded through autophagy in cancer cells under adhesion stress. Src--by controlling not only its own degradation but also that of other FAK-binding partners--allows cancer cell survival, suggesting a new therapeutic strategy.

Whole-cell models that explicitly represent all cellular components at the molecular level have the potential to predict phenotype from genotype. However, even for simple bacteria, whole-cell models will contain thousands of parameters, many of which are poorly characterized or unknown. New algorithms are needed to estimate these parameters and enable researchers to build increasingly comprehensive models. We organized the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 8 Whole-Cell Parameter Estimation Challenge to develop new parameter estimation algorithms for whole-cell models. We asked participants to identify a subset of parameters of a whole-cell model given the model's structure and in silico "experimental" data. Here we describe the challenge, the best performing methods, and new insights into the identifiability of whole-cell models. We also describe several valuable lessons we learned toward improving future challenges. Going forward, we believe that collaborative efforts supported by inexpensive cloud computing have the potential to solve whole-cell model parameter estimation.

In this guide, the authors outline the advantages of online eAssessment and examine the intellectual, technical, legal and cost issues that arise from its use. This guide outlines the major assessment types that are suitable for online assessment and makes a key distinction between formative and summative assessment. The focus is primarily on the latter since that is where the difficulties are most acute and robust systems most critical. A range of practical issues relating to the key stages in running a summative e-exam are explored and advice given on system requirements and on how to ensure that the exam runs smoothly when you ‘go live’. This section includes consideration of the way that using eAssessment might affect the standard setting and results analysis process. The section on future trends in online assessment explores possibilities such as computer adaptive testing and the automated assessment of free text answers. Finally, there is a consideration of the implications of these trends for management.

Recently, autophagy has been demonstrated to modulate tumourigenesis and the response to cancer therapy by regulating numerous cellular functions including maintenance of cell viability under metabolic stress, mitochondrial homeostasis, regulation of reactive oxygen species accumulation, maintenance of genomic integrity, protein quality control, establishment of oncogene-induced senescence and regulation of tissue inflammation and tumour immunogenicity. Autophagy determines these different phenotypes of the tumour cell via diverse effector mechanisms, either involving buffering of metabolism or sequestration of specific proteins and organelles from the cytosol. We argue that the key to understanding the net effect of autophagy in controlling tumourigenesis will be to functionally dissect these different effector mechanisms. This will be enabled by the identification of how these are regulated by intracellular signalling pathways. Further investigation of these pathways will reveal how individual autophagy outcomes might be selectively targeted for therapeutic gain.

Abstract Macroautophagy can regulate cell signalling and tumorigenesis via elusive molecular mechanisms. We establish a RAS mutant cancer cell model where the autophagy gene ATG5 is dispensable in A549 cells in vitro, yet promotes tumorigenesis in mice. ATG5 represses transcriptional activation by the TGFβ-SMAD gene regulatory pathway. However, autophagy does not terminate cytosolic signal transduction by TGFβ. Instead, we use proteomics to identify selective degradation of the signalling scaffold TRAF3. TRAF3 autophagy is driven by RAS and results in activation of the NF-κB family member RELB. We show that RELB represses TGFβ target promoters independently of DNA binding at NF-κB recognition sequences, instead binding with SMAD family member(s) at SMAD-response elements. Thus, autophagy antagonises TGFβ gene expression. Finally, autophagy-deficient A549 cells regain tumorigenicity upon SMAD4 knockdown. Thus, at least in this setting, a physiologic function for autophagic regulation of gene expression is tumour growth.

The management of hormone refractory prostate cancer remains controversial. Among the options, second-line hormonal therapy is commonly used. We investigated the efficacy of ketoconazole, an inhibitor of testicular and adrenal androgen biosynthesis, for treating patients with advanced hormone refractory prostate cancer.The study comprised 38 patients with progressive disease despite combined androgen blockade. Treatment consisted of intermediate-dose ketoconazole (300mg three times daily) and replacement hydrocortisone. Patients were monitored clinically and with serial psa measurements every 3 months. the principal endpoint was psa response.Of the 38 patients, 21 (55.3%) showed a decrease in PSA >50% (95% confidence interval 38.3%-71.4%) with a median duration of 6 months (range 3-48 months). A PSA reduction >50% was seen in 21 of 34 patients (61.8%) with established metastases. Thirteen patients (34.2%), all of whom had metastases, exhibited a PSA decrease >80% (95% confidence interval 19.6%-51.4%) with a median duration of 9 months (range 3-48 months). Age, PSA at diagnosis, Gleason score and bone scan result were not significantly associated with response to ketoconazole treatment in univariate or multivariate analyses. For the entire study group, the median time to progression was 5 months (range 0-27 months) and the median survival was 12 months (range 3-48 months). Overall, 12 patients (31.6%) reported toxicity related to intermediate-dose ketoconazole but only 6 patients (15.8%) discontinued therapy due to intolerable side effects.It is apparent from this study that a reasonable percentage of patients failing standard hormonal therapy respond favourably to intermediate-dose ketoconazole and that toxicity is mild. In the absence of studies demonstrating better survival with chemotherapy, we believe that a trial of ketoconazole should be considered when progression occurs on hormone therapy.

(Macro)autophagy is a membrane-trafficking process that serves to sequester cellular constituents in organelles termed autophagosomes, which target their degradation in the lysosome. Autophagy operates at basal levels in all cells where it serves as a homeostatic mechanism to maintain cellular integrity. The levels and cargoes of autophagy can, however, change in response to a variety of stimuli, and perturbations in autophagy are known to be involved in the aetiology of various human diseases. Autophagy must therefore be tightly controlled. We report here that the Drosophila cyclin-dependent kinase PITSLRE is a modulator of autophagy. Loss of the human PITSLRE orthologue, CDK11, initially appears to induce autophagy, but at later time points CDK11 is critically required for autophagic flux and cargo digestion. Since PITSLRE/CDK11 regulates autophagy in both Drosophila and human cells, this kinase represents a novel phylogenetically conserved component of the autophagy machinery.

Despite its prominence as the most frequently diagnosed solid tumor among men in the United States, relatively little is known about the etiology of prostate cancer. Furthermore, research into treatment strategies for prostate cancer continues to lag behind research for the other most common cancers. At the same time, however, the popularity of complementary therapies among prostate cancer patients continues to grow. In this article, we provide a critical review of the most recent evidence for dietary modifications, food supplements, and herbs in prostate cancer prevention and treatment. Despite encouraging data for some of these interventions, even the strongest proponents of complementary therapy agree that only randomized controlled trials can provide sufficient evidence on which to create universal guidelines. However, such trials are highly complex and expensive, and they require lengthy follow-up. Until such trials are completed, an opportunity exists for health care professionals to improve their knowledge and understanding of the current evidence for or against complementary therapy in prostate cancer.

While studies of ATG genes in knockout models led to an explosion of knowledge about the functions of autophagy components, the exact roles of LC3 and GABARAP proteins are still poorly understood. A major drawback for their understanding is that the available interactome data was largely acquired using overexpression systems. To overcome these limitations, we employed CRISPR/Cas9-based genome-editing to generate a panel of cells in which human ATG8 genes were tagged at their natural chromosomal locations with an N-terminal affinity epitope. This cellular resource was exemplarily employed to map endogenous GABARAPL2 protein complexes using interaction proteomics. This approach identified the ER-associated protein and lipid droplet (LD) biogenesis factor ACSL3 as a stabilizing GABARAPL2-binding partner. GABARAPL2 bound ACSL3 in a manner dependent on its LC3-interacting regions whose binding site in GABARAPL2 was required to recruit the latter to the ER. Through this interaction, the UFM1-activating enzyme UBA5 became anchored at the ER. Further, ACSL3 depletion and LD induction affected the abundance of several ufmylation components and ER-phagy. Together, we describe ACSL3 as novel regulator of the enigmatic UFM1 conjugation pathway.

The links between the p53/MDM2 pathway and the expression of pro-oncogenic immune inhibitory receptors in tumor cells are undefined. In this report, we evaluate whether there is p53 and/or MDM2 dependence in the expression of two key immune receptors, CD276 and PD-L1.Proximity ligation assays were used to quantify protein-protein interactions in situ in response to Nutlin-3. A panel of p53-null melanoma cells was created using CRISPR-Cas9 guide RNA mediated genetic ablation. Flow cytometric analyses were used to assess the impact of TP53 or ATG5 gene ablation, as well as the effects of Nutlin-3 and an ATM inhibitor on cell surface PD-L1 and CD276. Targeted siRNA was used to deplete CD276 to assess changes in cell cycle parameters by flow cytometry. A T-cell proliferation assay was used to assess activity of CD4+ T-cells as a function of ATG5 genotype.CD276 forms protein-protein interactions with MDM2 in response to Nutlin-3, similar to the known MDM2 interactors p53 and HSP70. Isogenic HCT116 p53-wt/null cancer cells demonstrated that CD276 is induced on the cell surface by Nutlin-3 in a p53-dependent manner. PD-L1 was also unexpectedly induced by Nutlin-3, but PD-L1 does not bind MDM2. The ATM inhibitor KU55993 reduced the levels of PD-L1 under conditions where Nutlin-3 induces PD-L1, indicating that MDM2 and ATM have opposing effects on PD-L1 steady-state levels. PD-L1 is also up-regulated in response to genetic ablation of TP53 in A375 melanoma cell clones under conditions in which CD276 remains unaffected. A549 cells with a deletion in the ATG5 gene up-regulated only PD-L1, further indicating that PD-L1 and CD276 are under distinct genetic control.Genetic inactivation of TP53, or the use of the MDM2 ligand Nutlin-3, alters the expression of the immune blockade receptors PD-L1 and CD276. The biological function of elevated CD276 is to promote altered cell cycle progression in response to Nutlin-3, whilst the major effect of elevated PD-L1 is T-cell suppression. These data indicate that TP53 gene status, ATM and MDM2 influence PD-L1 and CD276 paralogs on the cell surface. These data have implications for the use of drugs that target the p53 pathway as modifiers of immune checkpoint receptor expression.

The study aims were to determine the use of complementary therapies (CT) by men with prostate cancer, and to explore factors influencing CT use and attitudes toward CT use. A cross-sectional survey design was used in which a postal questionnaire was mailed to an eligible sample of 405 patients with prostate cancer receiving outpatient treatment in a London teaching hospital. The primary outcomes were the prevalence of CT use and the relationship between CT use and mental health status. Two hundred and ninety-four patients (73%) responded, of whom 25% were using CT. The most frequently used CTs were vitamins, low-fat diets, lycopene and green tea. Multivariate analyses revealed no differences in mental health scores between CT users and non-users. CT users were younger (OR 0.93, 95% CI 0.89-0.97) and were more likely to be receiving conservative management in the form of 'active surveillance' (OR 5.23, 95% CI 1.78-15.41) compared with non-users. Over half of the participants (55%) wanted to learn more about CT. Forty-three per cent of CT users had not informed any doctor about their CT use. Clinicians need to be aware of the prevalence of CT use amongst patients with prostate cancer, considering the potential harm that could be caused by interactions with conventional treatments.

Adenoviruses for gene or oncolytic therapy are under development. Notable among these strategies is adenoviral delivery of the tumor suppressor p53. Since all therapeutics have limitations in certain settings, we have undertaken retroviral suppressor screens to identify genes conferring resistance to adenovirus-delivered p53. These studies identified the tumor antigen LRRC15, which is frequently overexpressed in multiple tumor types, as a repressor of cell death due to adenoviral p53. LRRC15, however, does not impede p53 function per se but impedes adenoviral infection. Specifically, LRRC15 causes redistribution of the coxsackievirus-adenovirus receptor away from the cell surface. This effect is manifested in less adenoviral binding to the surfaces of LRRC15-expressing cells. This discovery, therefore, not only is important for understanding adenoviral biology but also has potentially important implications for adenovirus-based anticancer therapeutics.

<h2>Summary</h2> Targeting early-stage lung cancer is vital to improve survival. However, the mechanisms and components of the early tumor suppressor response in lung cancer are not well understood. In this report, we study the role of Toll-like receptor 2 (TLR2), a regulator of oncogene-induced senescence, which is a key tumor suppressor response in premalignancy. Using human lung cancer samples and genetically engineered mouse models, we show that TLR2 is active early in lung tumorigenesis, where it correlates with improved survival and clinical regression. Mechanistically, TLR2 impairs early lung cancer progression via activation of cell intrinsic cell cycle arrest pathways and the proinflammatory senescence-associated secretory phenotype (SASP). The SASP regulates non-cell autonomous anti-tumor responses, such as immune surveillance of premalignant cells, and we observe impaired myeloid cell recruitment to lung tumors after <i>Tlr2</i> loss. Last, we show that administration of a TLR2 agonist reduces lung tumor growth, highlighting TLR2 as a possible therapeutic target.

Technology has made life more complex, and mobile working (mWork) captures the way employees’ smart‐device use (e.g. smartphones, laptops etc.) can facilitate working during family time at home and what the effects of this use are. Engaging in mWork is expected to be detrimental to employee outcomes. In this study, mWork is explored as it relates to turnover intentions and work–family and family–work conflict, with conflict expected to mediate the influence on turnover. Furthermore, given the potential dynamics from gender and parental status, these are both included as moderators, and ultimately a moderated mediation model is tested. Using data from 419 New Zealand employees just after New Zealand's lockdown finished in May 2020, there is overall strong support found for the direct and mediation hypotheses. Overall, mWork influences turnover intentions by blurring the line between work and personal life (leading to higher work–family and family–work conflict), and these also influence turnover intentions.

How do I decide I am ill; how do I decide that my children are ill? How do I learn effective ways of conveying to others that I am ill? This book discusses the languages of illness which we use to present our discomforts to others through an exploration of the child's world of illness. It looks at how illness concepts are introduced to children, how the causes of illness and 'germ' rationales are incorporated into the socialisation of children, and how a particular morality about health and illness is expressed. Besides the analysis of the social context within which the children's views are developing, the book presents the children's own views from three years old up to thirteen. How we talk about illness can have as important consequences as the methods we use to cure it. This book persuades the reader to look more closely at the language of illness, allowing a reappraisal to medical practice, school health programmes and class teaching, health education and even the differences in health between the social classes. In this way it forges a link between physical medicine and psychotherapy, providing the developmental perspective of illness behaviour which has long been lacking.

Formative feedback that encourages self-directed learning in large class medical teaching is difficult to deliver. This study describes a new method, blueprinted feedback, and explores learner's responses to assess its appropriate use within medical science teaching.Mapping summative assessment items to their relevant learning objectives creates a blueprint which can be used on completion of the assessment to automatically create a list of objectives ranked by the attainment of the individual student. Two surveys targeted medical students in years 1, 2 and 3. The behaviour-based survey was released online several times, with 215 and 22 responses from year 2, and 187, 180 and 21 responses from year 3. The attitude-based survey was interviewer-administered and released once, with 22 responses from year 2 and 3, and 20 responses from year 1.88-96% of learners viewed the blueprinted feedback report, whilst 39% used the learning objectives to guide further learning. Females were significantly more likely to revisit learning objectives than males (p = 0.012). The most common reason for not continuing learning was a 'hurdle mentality' of focusing learning elsewhere once a module had been assessed.Blueprinted feedback contains the key characteristics required for effective feedback so that with further education and support concerning its use, it could become a highly useful tool for the individual and teacher.

The importance of selective macroautophagy/autophagy in cellular health is increasingly evident. The selective degradation of portions of the endoplasmic reticulum (ER), or reticulophagy, is an emerging example but requires further mechanistic detail and broad evidence of physiological relevance. In a recent study, we identified CCPG1, an ER-resident transmembrane protein that can bind to Atg8-family proteins and, independently and discretely, to RB1CC1/FIP200. Both of these interactions are required to facilitate CCPG1's function as a reticulophagy cargo receptor. CCPG1 transcripts are inducible by ER stress, providing a direct link between ER stress and reticulophagy. In vivo, CCPG1 prevents the hyper-accumulation of insoluble protein within the ER lumen of pancreatic acinar cells and alleviates ER stress. Accordingly, CCPG1 loss sensitizes the exocrine pancreas to tissue injury.

Good clinical practice is impossible without an understanding of the ways in which patients present their complaints. Patients have their own styles of coping and of expressing their concerns, and without a clear understanding of these the clinician may find successful and swift diagnosis and treatment much harder to achieve. Coping and Complaining provides essential guidance for clinicians on how to identify various coping styles, and how to improve the quality of discourse with people of different backgrounds and ages.Drawing on a diverse range of evidence from such areas as developmental psychology, and theories on learning and memory, Coping and Complaining provides essential information on identification of patients' coping styles, focusing on such areas as:· The latest developments in attachment theory· The neurobiology of emotional development, and the biology of language development· Primary processes in early development· Communication, role play, the moral order of the consultation, and emotional first aid· Consequences for preventive medicineCoping and Complaining presents stimulating new approaches to consultations with patients and creative new ways of looking at health promotion.

Several recent reports have demonstrated that autophagy is induced in response to hypoxia in cultured cells. However, the mechanism and consequence of hypoxia-induced autophagy remains unclear as there is no consensus between these studies. In our recent report we show that, in human cancer cells, hypoxia cooperates with growth factor signaling to facilitate a HIF1α-driven transcriptional response that promotes autophagy. Here we summarize these findings and set them in context of the findings of other groups, concluding that there are likely multiple routes to different forms of autophagy that serve different purposes downstream of hypoxia, depending upon the degree of stress and cellular context.

Objectives Waiting for prostate-specific antigen (PSA) results may create anxiety for patients. Recently developed “rapid” PSA assays have become available, which achieve laboratory sensitivity and specificity. The manufacturers claim these assays will help to reduce anxiety associated with PSA testing. The aim of this study was to test the hypothesis that rapid received PSA results reduce patient anxiety. Methods One hundred eighty-eight (n = 188) patients participated in a prospective randomized study. After obtaining informed consent, 67 patients were assigned to receive PSA results within 15 minutes of the blood sample being drawn, facilitating a discussion with the physician while in-clinic. One hundred twenty-one (n = 121) patients were assigned to receive their results within 1 to 4 days by telephone. Patients completed a baseline questionnaire about PSA testing and a follow-up questionnaire after they had received their PSA result by either method. Results There were no significant differences in patient demographics between the “rapid” and “delayed” PSA test groups. Baseline measurements of stress and anxiety were low and not significantly different between the groups. Receiving a rapid PSA result did not significantly reduce stress and anxiety compared with a delayed result. However, 89% of patients receiving a rapid result would elect to have this method again. Conclusions The rapid PSA test did not prove to alleviate stress or anxiety associated with receiving results. However, the cohort assigned to the rapid PSA test would prefer to have their results rapidly to facilitate discussion regarding their future management. Waiting for prostate-specific antigen (PSA) results may create anxiety for patients. Recently developed “rapid” PSA assays have become available, which achieve laboratory sensitivity and specificity. The manufacturers claim these assays will help to reduce anxiety associated with PSA testing. The aim of this study was to test the hypothesis that rapid received PSA results reduce patient anxiety. One hundred eighty-eight (n = 188) patients participated in a prospective randomized study. After obtaining informed consent, 67 patients were assigned to receive PSA results within 15 minutes of the blood sample being drawn, facilitating a discussion with the physician while in-clinic. One hundred twenty-one (n = 121) patients were assigned to receive their results within 1 to 4 days by telephone. Patients completed a baseline questionnaire about PSA testing and a follow-up questionnaire after they had received their PSA result by either method. There were no significant differences in patient demographics between the “rapid” and “delayed” PSA test groups. Baseline measurements of stress and anxiety were low and not significantly different between the groups. Receiving a rapid PSA result did not significantly reduce stress and anxiety compared with a delayed result. However, 89% of patients receiving a rapid result would elect to have this method again. The rapid PSA test did not prove to alleviate stress or anxiety associated with receiving results. However, the cohort assigned to the rapid PSA test would prefer to have their results rapidly to facilitate discussion regarding their future management.

ER stress-mediated induction of a new vertebrate-specific autophagy cargo receptor, CCPG1 (cell-cycle progression gene 1), drives degradation of endoplasmic reticulum. CCPG1 acts via ATG8-family interaction and, non-canonically, via discrete interactions with FIP200. CCPG1 ameliorates ER stress in the exocrine pancreas. This has potential implications for inflammation and cancer, discussed here.

Autophagy is an intracellular lysosomal degradation pathway by which cytoplasmic cargoes are removed to maintain cellular homeostasis. Monitoring autophagy flux is crucial to understand the autophagy process and its biological significance. However, assays to measure autophagy flux are either complex, low throughput or not sensitive enough for reliable quantitative results. Recently, ER-phagy has emerged as a physiologically relevant pathway to maintain ER homeostasis but the process is poorly understood, highlighting the need for tools to monitor ER-phagy flux. In this study, we validate the use of the signal-retaining autophagy indicator (SRAI), a fixable fluorescent probe recently generated and described to detect mitophagy, as a versatile, sensitive and convenient probe for monitoring ER-phagy. This includes the study of either general selective degradation of the endoplasmic reticulum (ER-phagy) or individual forms of ER-phagy involving specific cargo receptors (e.g., FAM134B, FAM134C, TEX264 and CCPG1). Crucially, we present a detailed protocol for the quantification of autophagic flux using automated microscopy and high throughput analysis. Overall, this probe provides a reliable and convenient tool for the measurement of ER-phagy.

Usability is widely recognised to be as important as functionality to the success of interactive computer systems. However, even where usability is considered seriously, the scope of thinking tends to be restricted to the so called 'average' users in typical office situations. Our aim in this chapter is to summarize some of the key findings in the literature on individual differences, exploring their implications for human-computer interaction. A framework comprising the characteristics of accessibility, usability and acceptability is presented to relate the salient factors to existing Human-Computer Interaction concepts. In doing this, the notion of 'user' is elaborated to reveal a much more complex and changing phenomenon than naive novice/expert or frequent/intermittent classifications suggest. In particular, we argue that we are all 'extra-ordinary users' when considered over time, though the term 'extra-ordinary users' is usually applied to disabled people (Edwards, 1994). We believe that the goal of User Interfaces for All is a timely and challenging concept which raises awareness of the inadvertent exclusion that too often results from nomothetic analysis and design. This chapter outlines a number of approaches that designers can take to accommodate individual differences, drawing on current research to illustrate some of the most promising directions being explored.

The role of macroautophagy (hereafter autophagy) in cancer biology and response to clinical intervention is complex. It is clear that autophagy is dysregulated in a wide variety of tumor settings, both during tumor initiation and progression, and in response to therapy. However, the pleiotropic mechanistic roles of autophagy in controlling cell behavior make it difficult to predict in a given tumor setting what the role of autophagy, and, by extension, the therapeutic outcome of targeting autophagy, might be. In this review we summarize the evidence in the literature supporting pro- and anti-tumorigenic and -therapeutic roles of autophagy in cancer. This overview encompasses roles of autophagy in nutrient management, cell death, cell senescence, regulation of proteotoxic stress and cellular homeostasis, regulation of tumor-host interactions and participation in changes in metabolism. We also try to understand, where possible, the mechanistic bases of these roles for autophagy. We specifically expand on the emerging role of genetically-engineered mouse models of cancer in shedding light on these issues in vivo.We also consider how any or all of the above functions of autophagy proteins might be targetable by extant or future classes of pharmacologic agents. We conclude by briefly exploring non-canonical roles for subsets of the key autophagy proteins in cellular processes, and how these might impact upon cancer.

There are strong pedagogical arguments in favor of adopting computer-based assessment. The risks of technical failure can be managed and are offset by improvements in cost-effectiveness and quality assurance capability. Academic, administrative, and technical leads at an appropriately senior level within an institution need to be identified, so that they can act as effective advocates. All stakeholder groups need to be represented in undertaking a detailed appraisal of requirements and shortlisting software based on core functionality, summative assessment life cycle needs, external compatibility, security, and usability. Any software that is a candidate for adoption should be trialed under simulated summative conditions, with all stakeholders having a voice in agreeing the optimum solution. Transfer to a new system should be carefully planned and communicated, with a programme of training established to maximize the success of adoption.

The degradation of the endoplasmic reticulum (ER) by autophagy (ER-phagy) regulates proteostasis. Two studies (An et al., Mol. Cell, 2019; Chino et al., Mol. Cell, 2019) have uncovered a new ER-phagy molecule, TEX264, yielding insight into how ER is packaged for degradation, and have illuminated the extent of redundancy between different ER-phagy ‘pathways’ in remodelling the ER proteome. The degradation of the endoplasmic reticulum (ER) by autophagy (ER-phagy) regulates proteostasis. Two studies (An et al., Mol. Cell, 2019; Chino et al., Mol. Cell, 2019) have uncovered a new ER-phagy molecule, TEX264, yielding insight into how ER is packaged for degradation, and have illuminated the extent of redundancy between different ER-phagy ‘pathways’ in remodelling the ER proteome.

Patients referred to adolescent psychiatric units have often been in contact with services for many years. When assessing for admission we consider why the previous approaches might have failed and how milieu therapy might be more effective as the priority treatment. We propose that the information provided by an adolescent's Transition to Adulthood Attachment Interview (TAAI) and the parents' Adult Attachment Interviews (AAI) leads to an especially productive case formulation. The Dynamic-Maturational Model of attachment and adaptation (DMM) uniquely provides a detailed understanding of an extended range of Type A and Type C strategies with modifiers that are useful for planning the milieu therapy, individual and family work. In addition, this case presentation illustrates the usefulness of understanding the phenomenon of "intruded negative affect".

As every urologist is aware, cancer of the prostate is a major public health threat. The American Cancer Society estimates that 189,000 American men will have been diagnosed with prostate cancer and that 30,200 will have died of the disease in 2002.1 It is the most common cancer diagnosed in men and the second leading cause of death from cancer in the United States, exceeded only by lung cancer.

Cell surface MHC-I can present tumor antigens to CD8+ T cells. In pancreatic cancer, selective autophagy instead reroutes MHC-I to lysosomes, using the ubiquitin-binding receptor NBR1, precluding T cell recognition. Accordingly, immune clearance of tumors can be facilitated by blocking autophagy. Cell surface MHC-I can present tumor antigens to CD8+ T cells. In pancreatic cancer, selective autophagy instead reroutes MHC-I to lysosomes, using the ubiquitin-binding receptor NBR1, precluding T cell recognition. Accordingly, immune clearance of tumors can be facilitated by blocking autophagy. In principle, cancers are targets of adaptive immunity. Mutant protein expression (and hyperexpression of unmutated proteins) can earmark tumor cells for destruction. Proteasomal processing of these proteins yields peptide antigens that are transported into the endoplasmic reticulum (ER) and then bound by the transmembrane major histocompatibility complex (MHC)-I, which traffics to the cell surface to present them to CD8+ cytotoxic T-lymphocytes (CTLs) and trigger cell killing. Indeed, immunotherapies seek to exploit tumor antigenicity. Dual immune checkpoint blockade (ICB) utilizes antibodies to block PD-L1 and CTLA-4, inhibitory cell surface molecules within the immune ecosystem. Often, tumors can evade immune recognition by mutating MHC-I, yielding intrinsic or acquired resistance to ICB. Pancreatic ductal adenocarcinoma (PDAC), which has a dismal prognosis, is non-responsive to dual ICB. However, mutation of MHC-I is rare in PDAC. Yamamoto et al., 2020Yamamoto K. Venida A. Yano J. Biancur D.E. Kakiuchi M. Gupta S. Sohn A.S.W. Mukhopadhyay S. Lin E.Y. Parker S.J. et al.Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I.Nature. 2020; 581: 100-105Crossref PubMed Scopus (394) Google Scholar now identify post-translational suppression of MHC-I function by selective autophagy as a means of immune resistance in this cancer (Figure 1). Macroautophagy (hereafter, simply “autophagy”) is characterized by the formation of double-membraned autophagic vesicles (AVs) that sequester parts of the cytoplasm and fuse with degradative lysosomes dependent upon the action of “core” autophagy gene products. Atop this, “cargo receptor” proteins can impart selectivity, acting as molecular bridges between core autophagy proteins and cytoplasmic cargos destined for degradation (organelles, proteins, or pathogens). Non-selective autophagy within the tumor stroma is known to provide paracrine metabolites to PDAC cells (Sousa et al., 2016Sousa C.M. Biancur D.E. Wang X. Halbrook C.J. Sherman M.H. Zhang L. Kremer D. Hwang R.F. Witkiewicz A.K. Ying H. et al.Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.Nature. 2016; 536: 479-483Crossref PubMed Scopus (640) Google Scholar). Furthermore, core autophagy genes in the tumor epithelium are required for PDAC growth (Yang et al., 2018Yang A. Herter-Sprie G. Zhang H. Lin E.Y. Biancur D. Wang X. Deng J. Hai J. Yang S. Wong K.K. Kimmelman A.C. Autophagy Sustains Pancreatic Cancer Growth through Both Cell-Autonomous and Nonautonomous Mechanisms.Cancer Discov. 2018; 8: 276-287Crossref PubMed Scopus (188) Google Scholar). Investigating the role of autophagy in this latter context, Yamamoto et al. first detected MHC-I within AVs and lysosomes in human PDAC lines and tissues. Importantly, silencing of various core autophagy genes required for AV formation consistently elevated cell surface MHC-I, as did inhibiting AV degradation using lysosome blockers, such as chloroquine. Thus, basal autophagy in PDAC cells sequesters MHC-I, preventing cell surface exposure. Given this mechanistic credence, the authors identified a role for Neighbor of BRCA1 (NBR1), a cargo receptor previously known for ubiquitylated protein aggregate removal, in binding MHC-I and facilitating sequestration. Furthermore, NBR1 required a ubiquitin-associated (UBA) domain for colocalization with MHC-I. Considering this, together with data showing polyubiquitylation of MHC-I, the authors propose sequestration mediated by ubiquitin tagging, as seen in other selective autophagy pathways. These findings raise further mechanistic questions. First, is polyubiquitylation of MHC-I itself required for NBR1 binding? Is the molecular complex composed of directly interacting NBR1-MHC-I, or does it contain as-yet-unidentified ubiquitylated proteins? Second, do specific cellular signaling pathways, including those controlling ubiquitin ligases, regulate modification of MHC-I, and are these corrupted in PDAC? Third, how is MHC-I, a transmembrane complex, physically trafficked to AVs from its site of residency in other cellular membranes? In principle, several membrane-bound organelles could potentially be targets for NBR1-mediated autophagy: ER/Golgi-derived fragments, endosomes, and plasma membrane-derived vesicles. Alternatively, MHC-I might be retro-translocated from membranes into the cytosol prior to sequestration or transferred directly into AV membranes from secretory pathway membranes. A potentially informative parallel comes from the observation that core autophagy genes are rate limiting for MHC-I internalization in dendritic cells (Loi et al., 2016Loi M. Müller A. Steinbach K. Niven J. Barreira da Silva R. Paul P. Ligeon L.A. Caruso A. Albrecht R.A. Becker A.C. et al.Macroautophagy Proteins Control MHC Class I Levels on Dendritic Cells and Shape Anti-viral CD8(+) T Cell Responses.Cell Rep. 2016; 15: 1076-1087Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Finally, it is a noteworthy observation that acute chloroquine treatment promotes cell surface localization of MHC-I, especially as this drug can be given to PDAC patients (Zeh et al., 2020Zeh H.J. Bahary N. Boone B.A. Singhi A.D. Miller-Ocuin J.L. Normolle D.P. Zureikat A.H. Hogg M.E. Bartlett D.L. Lee K.K. et al.A Randomized Phase II Preoperative Study of Autophagy Inhibition with High-Dose Hydroxychloroquine and Gemcitabine/Nab-Paclitaxel in Pancreatic Cancer Patients.Clin. Cancer Res. 2020; https://doi.org/10.1158/1078-0432.CCR-19-4042Crossref PubMed Scopus (84) Google Scholar). Chloroquine is canonically thought to disrupt AV (and endosome) degradation but not cargo sequestration. In PDAC cells, perhaps membrane trafficking is then stalled further upstream within the autophagy pathway, as an indirect consequence of chloroquine, or perhaps MHC-I can recycle to the cell surface from stabilized endosomes or AVs. The authors then probed the translational potential of their findings; they hypothesized that autophagy inhibition, and consequent MHC-I exposure, would sensitize PDAC to immune attack. First, they recapitulated MHC-I regulation by autophagy in murine PDAC cells of defined genetic background (C57BL/6) by “switching off” AV formation with a doxycycline-inducible dominant-negative core autophagy protein, ATG4B(C74A). Using this model, they showed that autophagy inhibition in vitro enhanced cell surface exposure of a model neoantigen (derived from ovalbumin expression) and killing by cognate CTLs. Next, cells were injected into immune-competent C57BL/6 mice to form tumors. In this syngeneic model, expression of endogenous tumor (neo)antigens is insufficient for graft rejection, enabling interrogation of potential immune resistance factors. Indeed, inhibiting autophagy reduced tumor establishment, dependent upon MHC-I and enhanced CTL infiltration. Most strikingly, dual ICB combined with ATG4B(C74A) induction or chloroquine treatment was synergistic in elimination of newly formed tumors. These results poise autophagy as a combination immunotherapy target in PDAC. How might one identify which PDAC patients would benefit from targeting autophagy? Autophagy in cancer, generally, has complex roles. In PDAC, anti-tumoral roles have been reported, albeit at early disease stages (Rosenfeldt et al., 2013Rosenfeldt M.T. O’Prey J. Morton J.P. Nixon C. MacKay G. Mrowinska A. Au A. Rai T.S. Zheng L. Ridgway R. et al.p53 status determines the role of autophagy in pancreatic tumour development.Nature. 2013; 504: 296-300Crossref PubMed Scopus (521) Google Scholar). Notably, though, NBR1 has thus far been ascribed predominantly pro-tumor functions (Marsh et al., 2020Marsh T. Kenific C.M. Suresh D. Gonzalez H. Shamir E.R. Mei W. Tankka A. Leidal A.M. Kalavacherla S. Woo K. et al.Autophagic Degradation of NBR1 Restricts Metastatic Outgrowth during Mammary Tumor Progression.Dev. Cell. 2020; 52: 591-604.e6Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). In PDAC, autophagic regulation of other immune functions will be a major consideration. For instance, in dendritic cells, MHC-II-mediated presentation of lysosomally derived peptides to CD4+ T cells actually requires autophagy (Münz, 2016Münz C. Autophagy Beyond Intracellular MHC Class II Antigen Presentation.Trends Immunol. 2016; 37: 755-763Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar); MHC-II action, potentially even from within the tumor epithelium, is emerging as a possible contributor to tumor immunogenicity (Johnson et al., 2018Johnson D.B. Nixon M.J. Wang Y. Wang D.Y. Castellanos E. Estrada M.V. Ericsson-Gonzalez P.I. Cote C.H. Salgado R. Sanchez V. et al.Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement.JCI Insight. 2018; 3: e120360Crossref PubMed Scopus (81) Google Scholar). Contrastingly, the authors highlight other desirable, potential effects of chloroquine on PDAC immune clearance, including enhanced T cell metabolism and anti-tumoral macrophage polarization. Down the line, intertumoral stratification of PDAC using predictive biomarkers for overall positive immune response to autophagy blockade will likely prove important. In this vein, how autophagy-mediated MHC-I regulation varies between existing and emergent molecular sub-classifications of PDAC (defined by omics studies), including intrinsically immunogenic tumors, would be informative (Collisson et al., 2019Collisson E.A. Bailey P. Chang D.K. Biankin A.V. Molecular subtypes of pancreatic cancer.Nat. Rev. Gastroenterol. Hepatol. 2019; 16: 207-220Crossref PubMed Scopus (345) Google Scholar). In conclusion, the authors describe a new selective autophagy mechanism targeting MHC-I that mediates immune evasion in PDAC, suggesting that some patients may gain future benefit from the anti-tumoral immune effects of targeting autophagy.

Castleman's disease is a rare disorder characterized by lymphoid hyperplasia. It may present as asymptomatic involvement of one lymph node group or as a multicentric disease with systemic features. We report a patient with Castleman's disease who presented with axillary lymphadenopathy associated with a solitary plasmacytoma originating from a rib. The affected rib was surgically resected and radical radiotherapy was subsequently administered to the axillary lymph nodes. In this particular case, a joint surgical and oncologic approach resulted in a successful outcome.

This chapter focuses on the use of computers for online summative assessment, in particular for objectively marked items. The aim of this chapter is to try and address the concerns of individuals wishing to pilot the introduction of online summative assessments in their own institutions. A five-stage development life cycle of online summative assessment—item development, quality assurance, item selection, examination delivery, and results analysis—is presented and discussed.

I present a rationale for two different types of in-patient child psychiatric unit: 24/7 intensive units and 24/5 child and family units. Intensive units address safety requirements. The developing personality of young people is at the centre of in-patient approaches on the child and family units. This requires attachment-informed practice. Families must always be involved and placement of units must facilitate their participation. The primary skill characterising these units is use of the milieu for therapy and combining this with family therapy. In other words, nurses and allied professionals need to be the dominant force in unit development, under the reflective guidance of consultants and clinical psychologists.

The scientific basis for practice in child psychiatry has developed apace. And has thrown up several quandries for an accepted paradigm for good practice anchored to the diagnostic schema developed in adult psychiatry. This paper hopes to stimulate discussion about where alternative paradigms might lead us on a path to precision medicine as applied to child psychiatry.

A new study reveals that the ROCK proteins play key roles in the formation of tumours in mice.

The major challenge for a clinician is integration of the wisdom available in the wide range of therapeutic paradigms available. I have found the principles guiding dialectic behaviour therapy (DBT; see Miller, Rathus, &amp; Linehan, 2007, for applying DBT to adolescents) extremely useful in my practice running a general adolescent unit; similarly, the understanding of the different information processing and learning principles associated with each of the Type A and C attachment strategies, as understood in dynamic maturational model (DMM), has guided me through the dark corners of treatment. Specifically, how does DMM inform practice of DBT? As a ‘DBTer’ might say, ‘Where is the wisdom in both points of view?’ Nevertheless, DMM is not primarily about treatment. It concerns how different ways of adapting to developmental contingencies bias perceptual propensities, and hence the information available for reflective brain function. Recognition of these twists to knowing what is going on can then be used to inform a variety of therapeutic approaches. The purpose of this article is to look for the signposts in DBT and DMM which together help navigate the comprehensive approach necessary in complicated therapy. In the process, hopefully some more general principles for addressing discomfited adolescents arise for informing future practice. Although many steer shy of using personality disorder diagnoses for adolescents, clinicians are nevertheless addressing, directly or indirectly, the personality development of all adolescents in treatment, regardless of their classical axis I diagnoses, including both those with developing emotional instability and a group of avoidant over-controlled adolescents, which in Norway is growing in prominence.

Modern technology and computing are playing an ever larger role in education in general and in medicine in particular. Computerisation of assessments has been used at a basic level for nearly 50 years, with optical mark readers (still used in many institutions, including on the Advanced Life Support and Advanced Trauma Life Support ® courses) first being used in the 1960s. A huge increase in the use of information technology as a teaching aid has been mirrored by an increase in its use in assessment. There are at least four major drivers behind this move towards computer-based assessment (CBA): efficiency, transparency, reliability and validity.

The therapeutic principles and practice on a psychiatric inpatient unit for adolescents are described. The practice has grown out of applications of ‘multisystemic treatment’ principles. The major challenges have been to ensure the formulation of concrete goals for treatment from the perspective of the adolescents and their parents, and ensuring that gains made on the ward can be generalized to local networks. The use of inpatient family therapy integrated with weekends at home, while the adolescent is an inpatient on the ward, is described.

Ant Colony Optimization (ACO) is a meta-heuristic that has been applied to a diverse set of optimization problems. Problems formulated using ACO have the beneficial quality that solutions are generally constructed making it possible to incorporate constraints during the construction process. Recently, problems in the telecommunications domain have utilized ACO heuristics for routing and fault localization. This paper describes an application of ACO to the network synthesis problem that shows promising results.

Knowledge has always been critically important to the development of aquaculture whether we are talking about the earliest aquaculture innovations starting in Asia or the more recent challenges confronting the sector worldwide. This panel reviewed selected national and regional case studies. Key topics for discussion include knowledge production and its communication and use (e.g. in new training and extension approaches) among the changing audiences (as aquaculture continues to attract an increasing variety of new stakeholders), and dealing with a widening set of change processes in recent times, often involving a complex mix of governance and social change challenges. We go on to suggest that aquaculture policy-makers, and stakeholders in general, need to better understand knowledge processes such as knowledge translation (implementation), knowledge networks (e.g. the role of farmers’ associations) and the use of knowledge platforms and brokers, all aimed at more effective dissemination and adoption of knowledge. Knowledge management by most stakeholders will become increasingly critical to the sustainable development of aquaculture and its movement towards attaining the goals set out in the Bangkok Declaration a decade back.

Erratum7 August 2012free access Src-dependent autophagic degradation of Ret in FAK-signalling-defective cancer cells Emma Sandilands Emma Sandilands Search for more papers by this author Bryan Serrels Bryan Serrels Search for more papers by this author Simon Wilkinson Simon Wilkinson Search for more papers by this author Margaret C Frame Margaret C Frame Search for more papers by this author Emma Sandilands Emma Sandilands Search for more papers by this author Bryan Serrels Bryan Serrels Search for more papers by this author Simon Wilkinson Simon Wilkinson Search for more papers by this author Margaret C Frame Margaret C Frame Search for more papers by this author Author Information Emma Sandilands, Bryan Serrels, Simon Wilkinson and Margaret C Frame EMBO Reports (2012)13:867-867https://doi.org/10.1038/embor.2012.126 This article corrects the following: Src-dependent autophagic degradation of Ret in FAK-signalling-defective cancer cells26 June 2012 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Correction to: EMBO reports (2012) 13, 733–740. doi:10.1038/embor.2012.92 In this article, published online 26 June 2012 and in the August issue, on page 739 in paragraph three, we expanded the acronym TK to read “thymidine kinase” rather than “tyrosine kinase”. The correct sentence should read: More work is needed to establish the full range of tyrosine kinases that are targeted to autophagosomes upon adhesion stress (beyond the scope here), which may permit identification of a range of tyrosine kinase inhibitors that could be of therapeutic value when used in conjunction with autophagy inhibitors. We apologize for this error. Next ArticlePrevious Article Volume 13Issue 91 September 2012In this issue RelatedDetailsLoading ...

The CHIC-Pilot project is a TERENA coordinated effort investigating the feasibility of setting up a large-scale distributed indexing service for searching Web-based research information. It brings together existing search services throughout Europe, integrating them into a coherent architecture. This paper describes both formal and de-facto standards used for various components in the CHIC-Pilot architecture, that support functionality ranging from a uniform search interface and query routing to robot-based gathering of resource descriptions and the handling of metadata. We also discuss techniques for interfacing components of search services using different standards and protocols to provide a unified service to the user.

Good clinical practice is impossible without an understanding of the ways in which patients present their complaints. Patients have their own styles of coping and of expressing their concerns, and without a clear understanding of these the clinician may find successful and swift diagnosis and treatment much harder to achieve. Coping and Complaining provides essential guidance for clinicians on how to identify various coping styles, and how to improve the quality of discourse with people of different backgrounds and ages.Drawing on a diverse range of evidence from such areas as developmental psychology, and theories on learning and memory, Coping and Complaining provides essential information on identification of patients' coping styles, focusing on such areas as:· The latest developments in attachment theory· The neurobiology of emotional development, and the biology of language development· Primary processes in early development· Communication, role play, the moral order of the consultation, and emotional first aid· Consequences for preventive medicineCoping and Complaining presents stimulating new approaches to consultations with patients and creative new ways of looking at health promotion.

A technique is described for eliciting information about family structure in terms of boundaries and alliances through an individual session with a child using the medium of drawing. An advantage of this approach is that the child's perspective is elicited through a medium with which the child feels familiar and at ease, which can subsequently be taken further with the child in or out of the family.

A study of Scottish nursery school children shows how they construct their world of illness using the images provided in the nursery and home. An awareness of children's perceptions of the world of illness enables professionals to establish helpful clinical relationships. The ways in which children handle images and respond to the questions of adults suggest that health education strategies should be reviewed.

In-patient treatment is a complex system of recursively interacting components. Patient characteristics interact with caregiver characteristics, home context and ward factors. Quality improvement requires primary focus on the interacting factors over which the ward itself potentially has influence. Ward practice has to integrate the demands of the hospital owner, the legal framework for treatment and what we know facilitates effective treatment plans. We describe how we have implemented a quality improvement system that addresses these interplaying influences in acute adolescent psychiatry in Norway. The process involved with this system (developed in the UK for child and adolescent psychiatric units) is independent of the organisational structure of the department and which alternative resources it has to rely on. It is independent of the characteristics of the patient population, although specific standards can be developed for local requirements.

Abstract Targeting early-stage lung cancer is vital to improve overall survival. We previously identified Toll-like receptor 2 (TLR2) as a regulator of oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP), both key for tumor suppression. Here, we demonstrate that TLR2 is widely expressed in human lung tumor epithelium where it correlates with improved survival and clinical regression. Using genetically engineered mouse models of lung cancer we have shown that Tlr2 is a tumor suppressor in lung cancer initiation via regulation of proliferation and the SASP. The SASP is integral in the regulation of immune surveillance of premalignant cells, and we observe impaired myeloid derived immune surveillance following Tlr2 loss. Lastly, we show that administration of a synthetic Tlr2 agonist significantly reduces preinvasive lung tumor growth. Our data highlight an unexpected tumor surveillance pathway in early-stage lung cancer with therapeutic potential. Statement of significance Lung cancer is a major cancer of unmet need. This study identifies a novel tumor suppressor mechanism in lung cancer. Not only does this highlight a potential therapeutic target for early-stage disease but also multiple secreted candidate biomarkers that could be exploited to augment lung cancer screening approaches.

rxgk is a security class for the RX RPC protocol. It uses the GSSAPI framework to provide authentication, confidentiality and integrity protection. This document provides a general description of rxgk. A further document will provide details of integration with specific RX applications.

The diagnosis of a life-changing illness tests the faith of even the most committed Christian. In this paper two Anglican clergy who have both received life-changing diagnoses reflect theologically upon their experience and draw conclusions about the relationship between sickness, sin, evil and the goodness of God.

This document describes how the new GSSAPI-based rxgk security class for RX is integrated with the AFS application protocol. It describes a number of extensions to the basic rxgk protocol, clarifies a number of implementation issues, and provides values for the application- specific elements of rxgk.

<h3>Objectives</h3> To describe an update of the cancer incidence and mortality of workers at a Scottish semiconductor manufacturing facility to assess potential workplace cancer risks. <h3>Methods</h3> Company records had been used to identify a cohort of 4388 workers employed at the facility between 1970 and 1999. Subjects were flagged against National Health Service records for notification of cancer registrations and deaths. Standardised mortality (to end 2007) and cancer registration (to end 2006) ratios (SMRs and SRRs) were calculated for cancer site groups of a priori interest, comparing with Scottish rates adjusted for local deprivation status. <h3>Results</h3> There was a substantial deficit of mortality overall, particularly among men, compatible, at least in part, with a healthy work effect: SMR% (males) 45, 95% CI 34 to 57; SMR% (females) 73, 95% CI 58 to 90. Total cancer registrations were consistent with expectation for men (SRR% 90, 95% CI 69 to 116) and women (SRR% 102, 95% CI 85 to 122). SRRs for four cancer sites highlighted in an earlier analysis (lung, stomach and breast cancer in women; and brain cancer in men) were not statistically significantly elevated overall; neither were those for any other cancer site group. Analyses of cohort subgroups (including a group more likely to have worked in areas using carcinogens) by time since first employment, and analyses by duration of employment did not reveal any associations suggestive of a workplace effect on cancer rates. <h3>Conclusions</h3> This analysis does not support earlier concerns about a possible link between working at the facility and increased risks of cancer.

<h3>Objectives</h3> HSE9s 2001 report on cancer in a Scottish cohort of semiconductor manufacturing workers showed some statistically significant results, suggestive of increased risks. Recently, the follow-up in the cohort was extended. We report on a case-based study to investigate these suggestions. <h3>Methods</h3> From the extended follow-up, cases of breast, stomach and lung cancer in women, and of brain cancer in men were identified. It was planned that the lung and breast cancer cases would be interviewed and compared with matched controls, and that the rarer stomach and brain cancers would be examined case-only. A questionnaire was designed to collect detailed employment histories within the factory and elsewhere, information relevant to possible asbestos exposure, and lifestyle and environmental factors. A historical hygiene assessment was carried out at the factory, to inform construction of a job-exposure matrix. <h3>Results</h3> Attempts to recruit cases (or proxy respondents) were only partially successful; as a result, the lung cancers element was converted to a case-only study. Comparison with controls was possible for only 20 breast cancer cases (including 7 proxy respondents). From an extensive programme of conditional logistic analyses, statistical significance was achieved for exposure to arsenic compounds, antimony trioxide and sulphuric acid mist and to gases in general, but only in a few of the analyses. Examination of proxy responses for stomach, lung and brain cancers did not suggest any common workplace factors for any of these outcomes. <h3>Conclusions</h3> We interpreted this evidence as not supportive of an occupational risk for any of the cancers.

This chapter focuses on the use of computers for online summative assessment, in particular for objectively marked items. The aim of this chapter is to try and address the concerns of individuals wishing to pilot the introduction of online summative assessments in their own institutions. A five-stage development life cycle of online summative assessment—item development, quality assurance, item selection, examination delivery, and results analysis—is presented and discussed. Request access from your librarian to read this chapter's full text.

CancerFocal adhesion kinase (FAK) Cell culture studies suggest combining FAK and autophagy inhibitors could help treat cancer.In squamous carcinoma cells from Fak knockout mice, autophagy inhibitors increased apoptosis compared with no treatment.Next steps include identifying interactions between FAK and regulators of autophagy.CureFAKtor Pharmaceuticals LLC's FAK and VEGF receptor 3 (FLT4; VEGFR-3) inhibitor, CFAK-C4, is in preclinical development for pancreatic cancer.Teva Pharmaceutical Industries Ltd. 's anaplastic lymphoma kinase (ALK) and FAK inhibitor, CEP-37440, is in preclinical development for multiple cancers.Teva gained rights to the compound through its acquisition of Cephalon Inc. in 2011.

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With the impending formation of the foundation to house OpenAFS, the increasing pace of OpenAFS development, and the emergence of other AFS implementations, there is a growing need for a more formal, independent, standardisation body. This document seeks to define an initial form for that body.

This document describes an additional set of RX remote procedure calls which may be used to managed extended authenticated names within the AFS-3 basic overseer service's SuperUser list

Gjennom livet utvikler vi et bredt spekter av personlige strategier som vi anvender i stressende situasjoner. Med utgangspunkt i tilknytningsteori gjør forfatteren rede for hvordan mestringstrategier dannes, og hvilke utfordringer vi står overfor i møte med pasientenes strategier for å takle hospitalisering og sykdom.

After a house physician job at the Queen Elizabeth Hospital, Birmingham, Ian Wilkinson joined a general practice in the …

Autophagy of the endoplasmic reticulum, or ER-phagy, maintains the homeostasis of the secretory pathway. This is particularly prominent in specialized secretory cells such as the acinar cells of the exocrine pancreas. The role for such a homeostatic pathway during ageing of mammals is modelled best by in vivo genetic or pharmacologic intervention in mice. This is due to the paucity of cellular models that can maintain acinar identity outside of an animal. Here we present methods for isolation of soluble and insoluble protein fractions of ER luminal proteins from the pancreas, alongside RNA. Analysis of these macromolecules allows inference of changes in ER luminal proteostasis upon autophagy-targeted interventions. These methods will likely be more widely applicable, beyond autophagy research.

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