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Purpose: Elevated lipogenesis regulated by sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor playing a central role in lipid metabolism, is a novel characteristic of glioblastoma (GBM). The aim of this study was to identify effective approaches to suppress GBM growth by inhibition of SREBP-1. As SREBP activation is negatively regulated by endoplasmic reticulum (ER) cholesterol, we sought to determine whether suppression of sterol O-acyltransferase (SOAT), a key enzyme converting ER cholesterol to cholesterol esters (CE) to store in lipid droplets (LDs), effectively suppressed SREBP-1 and blocked GBM growth.Experimental Design: The presence of LDs in glioma patient tumor tissues was analyzed using immunofluorescence, immunohistochemistry, and electronic microscopy. Western blotting and real-time PCR were performed to analyze protein levels and gene expression of GBM cells, respectively. Intracranial GBM xenografts were used to determine the effects of genetically silencing SOAT1 and SREBP-1 on tumor growth.Results: Our study unraveled that cholesterol esterification and LD formation are signature of GBM, and human patients with glioma possess elevated LDs that correlate with GBM progression and poor survival. We revealed that SOAT1 is highly expressed in GBM and functions as a key player in controlling the cholesterol esterification and storage in GBM. Targeting SOAT1 suppresses GBM growth and prolongs survival in xenograft models via inhibition of SREBP-1–regulated lipid synthesis.Conclusions: Cholesterol esterification and storage in LDs are novel characteristics of GBM, and inhibiting SOAT1 to block cholesterol esterification is a promising therapeutic strategy to treat GBM by suppressing SREBP-1. Clin Cancer Res; 22(21); 5337–48. ©2016 AACR.

Supplementary Figures S1-S8

Purpose:To examine the effect of oncolytic herpes simplex virus (oHSV) on NOTCH signaling in central nervous system tumors.Experimental Design:Bioluminescence imaging, reverse phase protein array proteomics, fluorescence microscopy, reporter assays, and molecular biology approaches were used to evaluate NOTCH signaling. Orthotopic glioma-mouse models were utilized to evaluate effects in vivo.Results:We have identified that herpes simplex virus-1 (HSV-1; oncolytic and wild-type)-infected glioma cells induce NOTCH signaling, from inside of infected cells into adjacent tumor cells (inside out signaling). This was canonical NOTCH signaling, which resulted in activation of RBPJ-dependent transcriptional activity that could be rescued with dnMAML. High-throughput screening of HSV-1–encoded cDNA and miRNA libraries further uncovered that HSV-1 miR-H16 induced NOTCH signaling. We further identified that factor inhibiting HIF-1 (FIH-1) is a direct target of miR-H16, and that FIH-1 downregulation by virus encoded miR-H16 induces NOTCH activity. FIH-1 binding to Mib1 has been reported, but this is the first report that shows FIH-1 sequester Mib1 to suppress NOTCH activation. We observed that FIH-1 degradation induced NOTCH ligand ubiquitination and NOTCH activity. REMBRANDT and The Cancer Genome Atlas data analysis also uncovered a significant negative regulation between FIH-1 and NOTCH. Furthermore, combination of oHSV with NOTCH-blocking gamma secretase inhibitor (GSI) had a therapeutic advantage in two different intracranial glioma models treated with oncolytic HSV, without affecting safety profile of the virus in vivo.Conclusions:To our knowledge this is the first report to identify impact of HSV-1 on NOTCH signaling and highlights the significance of combining oHSV and GSI for glioblastoma therapy.

Supplementary Figure 1. TIP47 staining represents lipid droplets in cancer cell lines. Supplementary Figure 2. LD number is correlated with Ki67 positive percentage in GBM patient tumor tissues. Supplementary Figure 3. SOAT1 is majorly expressed in GBM patient tumor tissues and cell lines. Supplementary Figure 4. Genetic or pharmacologic inhibition of SOAT1 suppresses lipid droplet formation in GBM cells. Supplementary Figure 5. Genetic or pharmacologic inhibition of SOAT1 does not significantly advance GBM cell cholesterol levels. Supplementary Figure 6. Genetic or pharmacologic inhibition of SOAT1 suppresses SREBP-1 activation and reduces the expression of its downstream targets. Supplementary Figure 7. Inhibition of SOAT1 has no inhibitory effect on LDL uptake.

Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces interferons (IFNs) to activate resistance mechanisms. Applying unbiased phylogenetic analysis, we show that interleukin-24 (IL24) is among the closest evolutionary homologs to the IFN family and shares a common ancestral origin. However, in contrast to IFNs, IL24 induction occurs specifically in barrier epithelial progenitors after injury and is independent of microbiome or adaptive immunity. Surprisingly,Il24ablation impedes not only epidermal proliferation and re-epithelialization, but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopicIl24 induction in homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, sustainedIl24expression depends upon both IL24 receptor/STAT3 signaling and also hypoxia-stabilized HIF1α, which converge following injury. Thus, parallel to the IFN-mediated innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL24-mediated tissue repair.

Cells encountering stressful situations activate the integrated stress response (ISR) pathway to limit protein synthesis and redirect translation to better cope. The ISR has also been implicated in cancers, but redundancies in the stress-sensing kinases that trigger the ISR have posed hurdles to dissecting physiological relevance. To overcome this challenge, we targeted the regulatory node of these kinases, namely, the S51 phosphorylation site of eukaryotic translation initiation factor eIF2α and genetically replaced eIF2α with eIF2α-S51A in mouse squamous cell carcinoma (SCC) stem cells of skin. While inconsequential under normal growth conditions, the vulnerability of this ISR-null state was unveiled when SCC stem cells experienced proteotoxic stress. Seeking mechanistic insights into the protective roles of the ISR, we combined ribosome profiling and functional approaches to identify and probe the functional importance of translational differences between ISR-competent and ISR-null SCC stem cells when exposed to proteotoxic stress. In doing so, we learned that the ISR redirects translation to centrosomal proteins that orchestrate the microtubule dynamics needed to efficiently concentrate unfolded proteins at the microtubule-organizing center so that they can be cleared by the perinuclear degradation machinery. Thus, rather than merely maintaining survival during proteotoxic stress, the ISR also functions in promoting cellular recovery once the stress has subsided. Remarkably, this molecular program is unique to transformed skin stem cells, hence exposing a vulnerability in cancer that could be exploited therapeutically.

Human adenosine deaminase acting on RNA 1 (ADAR1) catalyzes adenosine-to-inosine deamination reactions on double-stranded RNA molecules to regulate cellular responses to endogenous and exogenous RNA. Defective ADAR1 editing leads to disorders such as Aicardi-Goutières syndrome, an autoinflammatory disease that manifests in the brain and skin, and dyschromatosis symmetrica hereditaria, a skin pigmentation disorder. Two ADAR1 protein isoforms, p150 (150 kDa) and p110 (110 kDa), are expressed and can edit RNA, but the contribution of each isoform to the editing landscape remains unclear, largely because of the challenges in expressing p150 without p110. In this study, we demonstrate that p110 is coexpressed with p150 from the canonical p150-encoding mRNA due to leaky ribosome scanning downstream of the p150 start codon. The presence of a strong Kozak consensus context surrounding the p110 start codon suggests the p150 mRNA is optimized to leak p110 alongside expression of p150. To reduce leaky scanning and translation initiation at the p110 start codon, we introduced synonymous mutations in the coding region between the p150 and p110 start codons. Cells expressing p150 constructs with these mutations produced significantly reduced levels of p110. Editing analysis of total RNA from ADAR1 knockout cells reconstituted separately with modified p150 and p110 revealed that more than half of the A-to-I edit sites are selectively edited by p150, and the other half are edited by either p150 or p110. This method of isoform-selective editing analysis, making use of the modified p150, has the potential to be adapted for other cellular contexts.

Objective To investigate systematically the presence of the Babinski sign in paintings of the Christ Child by the greatest painters of the Renaissance. Design Observational analysis. Setting Large collection of paintings depicting the Christ Child from Flemish, Rhenish, and Italian schools between 1400 and 1550 CE, searched using published catalogues and Google. Study sample 302 Renaissance paintings (by 19 painters) depicting the Christ Child. Main outcome measure Babinski sign, defined as a hallux extension with an amplitude greater than 30°. The presence of foot sole stimulation was also noted. Results An unquestionable upgoing toe was apparent in 90 (30%) of the 302 paintings. The Babinski sign was present in more than 60% of Christ Child paintings by Rogier van der Weyden, Hans Memling, Martin Schongauer, and Matthias Grünewald. A bilateral Babinski sign was observed in three paintings. Stimulation of the sole was noted in 48/90 (53%) paintings and was always present in paintings by Andrea del Verrocchio, Leonardo da Vinci, and Giorgione. No association existed between the presence of the Babinski sign and the period during which the painter was active. Conclusions Four main factors were noted in relation to the representation of the Babinski sign in paintings of the Christ Child: the physiological toe phenomenon in infants, the representation of the nudity of the Christ by painters during the 15th century to demonstrate the incarnation, Renaissance painters’ need for precise observation of anatomy, and the desire of some Rhenish and Flemish painters to depict very realistic details. Italian Renaissance painters, whether Mannerist or not, tended to idealise the beauty of human body, and they often did not reproduce the Babinski sign.

Although the number of severely ill people is declining in some epicenters, there is a risk of a second wave of COVID-19 infection (Shungquin and Yuanyuan 2020) with a large number of patients who ...

Tissue stem cells are the cell of origin for many malignancies. Metabolites regulate the balance between self-renewal and differentiation, but whether endogenous metabolic pathways or nutrient availability predispose stem cells towards transformation remains unknown. Here, we address this question in epidermal stem cells (EpdSCs), which are a cell of origin for squamous cell carcinoma. We find that oncogenic EpdSCs are serine auxotrophs whose growth and self-renewal require abundant exogenous serine. When extracellular serine is limited, EpdSCs activate de novo serine synthesis, which in turn stimulates α-ketoglutarate-dependent dioxygenases that remove the repressive histone modification H3K27me3 and activate differentiation programmes. Accordingly, serine starvation or enforced α-ketoglutarate production antagonizes squamous cell carcinoma growth. Conversely, blocking serine synthesis or repressing α-ketoglutarate-driven demethylation facilitates malignant progression. Together, these findings reveal that extracellular serine is a critical determinant of EpdSC fate and provide insight into how nutrient availability is integrated with stem cell fate decisions during tumour initiation.

It is two hundred years since James Parkinson published An Essay on the Shaking Palsy. While his monograph continues to be acclaimed for its precedence and clarity of description, what is often overlooked is the originality of Parkinson’s ideas. We show that he appreciated the weakness of the systematic eighteenth century nosologies, which presupposed that medical species, the building blocks of these Linnaean taxonomic schemes, were as distinct as plant and animal species; and that Parkinson made a conceptual leap about combinations of clinical phenomena in recurring patterns, now recognized to be one of the germs of neurological thinking about syndromes. The Essay’s written style underpins another aspect of significance to contemporary neurological practice—an inherent intellectual humility. In this commemorative year we locate the continuing importance of the related notions of syndrome and disease in successive frameworks of knowledge about the Shaking Palsy. Syndrome and disease are interpreted as dual character concepts, one clinically-based and the other restricted to pathophysiological causation. They both remain fundamental to understanding Parkinson’s syndrome-disease today

Purpose: To examine the effect of oncolytic herpes simplex virus (oHSV) on NOTCH signaling in central nervous system tumors. Experimental Design: Bioluminescence imaging, reverse phase protein array proteomics, fluorescence microscopy, reporter assays, and molecular biology approaches were used to evaluate NOTCH signaling. Orthotopic glioma-mouse models were utilized to evaluate effects in vivo. Results: We have identified that herpes simplex virus-1 (HSV-1; oncolytic and wild-type)-infected glioma cells induce NOTCH signaling, from inside of infected cells into adjacent tumor cells (inside out signaling). This was canonical NOTCH signaling, which resulted in activation of RBPJ-dependent transcriptional activity that could be rescued with dnMAML. High-throughput screening of HSV-1–encoded cDNA and miRNA libraries further uncovered that HSV-1 miR-H16 induced NOTCH signaling. We further identified that factor inhibiting HIF-1 (FIH-1) is a direct target of miR-H16, and that FIH-1 downregulation by virus encoded miR-H16 induces NOTCH activity. FIH-1 binding to Mib1 has been reported, but this is the first report that shows FIH-1 sequester Mib1 to suppress NOTCH activation. We observed that FIH-1 degradation induced NOTCH ligand ubiquitination and NOTCH activity. REMBRANDT and The Cancer Genome Atlas data analysis also uncovered a significant negative regulation between FIH-1 and NOTCH. Furthermore, combination of oHSV with NOTCH-blocking gamma secretase inhibitor (GSI) had a therapeutic advantage in two different intracranial glioma models treated with oncolytic HSV, without affecting safety profile of the virus in vivo. Conclusions: To our knowledge this is the first report to identify impact of HSV-1 on NOTCH signaling and highlights the significance of combining oHSV and GSI for glioblastoma therapy.

What you need to know Eliciting the deep tendon reflexes is a vital component of medical assessments in general practice (where 9% of medical problems are believed to be neurological in origin1) and in hospital (where 10-20% of admissions have a primary neurological problem2). Reflex testing contributes to accurate bedside diagnosis in many cases of neuromuscular disease, providing localising diagnostic information that cannot be obtained by any other method (including clinical neurophysiological and neuroradiological investigations). It can be helpful in deciding if neurological, neurosurgical, or orthopaedic referral is required. This article briefly describes the clinical and pathological rationales for reflex testing and gives practical tips on when and how to elicit the deep tendon reflexes. When a tendon is tapped briskly its muscle contracts as a consequence of a synchronous volley of afferent impulses from the primary sensory endings of the muscle spindles in the stretched muscle. This involves a two neurone reflex in the spinal or brain stem segment that innervates the muscle (fig 1). At the same time, neurones modulated by descending corticospinal fibres are stimulated which activate opposing muscle groups around the joint dampening the resulting jerk. Fig 1 The reflex arc Patients presenting with motor or sensory symptoms in the limbs should have their reflexes tested to help distinguish between a lower motor neurone lesion (due to damage in the final common pathway that connects the anterior horn cells of the spinal cord with muscles via the nerve roots, plexuses, peripheral nerves, and neuromuscular junction) and …

Is it a pump or is it a pearl?Is it a muscle or is it a whale?Is that a scar or is it a medal?Heart symbolism goes beyond religious iconography and pop culture; it is imbued with experiential significance. But how to reconcile stories of heart disease and patients’ perceptions of their hearts with the more technical, anatomical and physiological dimensions of the organ? And why? These were the two fundamental questions underpinning a recent workshop exploring the possibility of a “narrative cardiology” (a tentative definition of a research and teaching area, itself explored during the event), which could help us find answers to these questions. The meeting (Figure 1) was held in Bristol at the Chocolate Factory, a creative space including artist studios in the city centre, and organised by the Bristol Heart Institute (GB) in collaboration with the Department of English (MV) of the University of Bristol with the support of the British Heart Foundation and under the auspices of the Centre for Health Humanities and Science (http://www.bristol.ac.uk/arts/research/centres/health-humanities-science/).

Resistance to genotoxic therapies is a primary cause of treatment failure and tumor recurrence. The underlying mechanisms that activate the DNA damage response (DDR) and allow cancer cells to escape the lethal effects of genotoxic therapies remain unclear. Here, we uncover an unexpected mechanism through which pyruvate kinase M2 (PKM2), the highly expressed PK isoform in cancer cells and a master regulator of cancer metabolic reprogramming, integrates with the DDR to directly promote DNA double-strand break (DSB) repair. In response to ionizing radiation and oxidative stress, ATM phosphorylates PKM2 at T328 resulting in its nuclear accumulation. pT328-PKM2 is required and sufficient to promote homologous recombination (HR)-mediated DNA DSB repair through phosphorylation of CtBP-interacting protein (CtIP) on T126 to increase CtIP's recruitment at DSBs and resection of DNA ends. Disruption of the ATM-PKM2-CtIP axis sensitizes cancer cells to a variety of DNA-damaging agents and PARP1 inhibition. Furthermore, increased nuclear pT328-PKM2 level is associated with significantly worse survival in glioblastoma patients. Combined, these data advocate the use of PKM2-targeting strategies as a means to not only disrupt cancer metabolism but also inhibit an important mechanism of resistance to genotoxic therapies.

Narrative became a concept of great versatility and fluidity in the second half of the twentieth century, configuring multi-dimensional understandings and meanings in healthcare. The literary and social theorist Martin Kreiswirth speaks of ‘a massive and unprecedented eruption of interest in narrative and in theorizing about narrative’ in the period, which resulted in stories and fragments of stories gaining significant conceptual traction in many discourses and practices. Not until narrative began to be credited with such multi-disciplinary capacities were claims for a pluripotential role in medicine explicitly formulated. Yet in attempting to respond to human needs incarnated in language, narrativity and medicine have long been co-implicated. If ‘the chief characteristic of human life is that it is always full of events which ultimately can be told as a story,’ as Hannah Arendt argued, narrativity is a precondition of epitomising and reflecting on illness.6

This chapter examines the status James Parkinson accorded "nonmotor" features of the malady set out in his 1817 Essay. In reading the Essay through the lens of this recently developed dichotomy I use "nonmotor" to mean the application of a late 20th-century category to a 200 year old account, whereas nonmotor designates application of the concept to contemporary understanding. While Parkinson granted "motor" components of the malady high definitional visibility, the Essay shows he was also attentive to patients' overall well-being and noticed some "nonmotor" aspects of the malady, in particular, constipation, interrupted speech, and difficulties with saliva and swallowing. He appears to have granted these features more than incidental status, especially in assessing variant pictures of the Shaking Palsy.

Modern clinical case reporting takes the form of problem-solution narratives that redescribe symptoms in terms of disease categories. Authored almost always by those who have played a part in the medical assessment of the patient, reports historicise the salient details of an individual's illness as a complex effect of identifiable antecedent causes. Candidate hypotheses linking illness to pathological mechanisms are suggested by the patient’s experience, and by data that emerge from clinical examination and investigation. Observational and interpretive statements from these considerations are fitted into a temporally inflected account of the patient’s medical condition, configured from the vantage point of hindsight. Drawing on established forms of deferred telling, readers are invited to follow a story that drip-feeds a mixture of contingent and non-incidental information into the account, which engenders and frustrates curiosity, creates expectations, and challenges powers of reasoning and pattern recognition. Whereas case reporting once favoured memoir, the sentimental tale and eccentric biography as the means by which its historical narrative was cast, the preferred genres of contemporary case reporting include detective fiction, and puzzle and riddle narratives, formats that conceptualise the medical consultation in narrow problem-solution terms.

We are just beginning to understand how translational control affects tumour initiation and malignancy. Here we use an epidermis-specific, in vivo ribosome profiling strategy to investigate the translational landscape during the transition from normal homeostasis to malignancy. Using a mouse model of inducible SOX2, which is broadly expressed in oncogenic RAS-associated cancers, we show that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. During tumour initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing the translational efficiency of oncogenic mRNAs. An in vivo RNA interference screen of translational regulators revealed that depletion of conventional eIF2 complexes has adverse effects on normal but not oncogenic growth. Conversely, the alternative initiation factor eIF2A is essential for cancer progression, during which it mediates initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a role for the translation of 5' untranslated regions in cancer, and expose new targets for therapeutic intervention.

INTRODUCTION Glioblastomas (GBMs) are resistant to traditional therapies, and new treatment is urgently needed. NOTCH signaling is highly activated in glioma and activated NOTCH signaling is associated with increased tumor growth and therapeutic resistance. Effect of oncolytic virus therapy on NOTCH signaling activation has not been reported to our knowledge. METHODS Western blotting, real time Q-PCR, reporter assay, and bioluminescence mice imaging were used to evaluate oHSV-mediated activation of NOTCH signaling. High throughput analysis of HSV-1-encoded microRNAs and genes were performed to identify the activator of NOTCH signaling, and in silico analysis, 3’ untranslated region (3’UTR) assay, and immunoprecipitation were used to uncover the down-stream signaling. Anti-tumor efficacy of NOTCH inhibitor, gamma-secretase inhibitor (GSI) combined with oHSV was evaluated using intracranial glioma-bearing mouse xenografts. RESULTS oHSV infection induced NOTCH activity in glioma PDX cells. High throughput analysis uncovered this to be due to HSV-1-encoded miR-H16 (miR-H16). 3’UTR analysis of Factor Inhibiting HIF-1 (FIH-1) indicated miR-H16 directly target FIH-1 and repress its protein expression. Immunoprecipitation analysis also uncovered that FIH-1 reduction liberated Mild bomb 1 (Mib1) from FIH-1 mediated sequestration, permitting it to activate NOTCH signaling by ubiquitination of NOTCH ligands. Forced expression of either antago-miR-H16 or FIH-1 attenuated the oHSV-induced NOTCH activation. Furthermore, oHSV therapy-induced activation of NOTCH signaling sensitized tumors to GSI, resulting in significantly improved therapeutic response to oHSV therapy and prolonged the survival in several intracranial GBM xenografts. CONCLUSION In this study, we identified the mechanism of oHSV therapy-mediated activation of NOTCH signaling, and showed the therapeutic benefit of combining oHSV with GSI.

Last year saw the 100th anniversary of the death of Joseph Lister FRCS PRS (1827–1912), and two Lister commemorative events, in London and Edinburgh.[1][1] This issue of Notes and Records is devoted to new scholarship on Lister's surgical science and discovery of antisepsis, and brings together a

Purpose: Both the proteasome inhibitor bortezomib and an oncolytic herpes simplex virus-1 (oHSV)–expressing GM-CSF are currently FDA approved. Although proteasome blockade can increase oHSV replication, immunologic consequences, and consequent immunotherapy potential are unknown. In this study, we investigated the impact of bortezomib combined with oHSV on tumor cell death and sensitivity to natural killer (NK) cell immunotherapy. Experimental Design: Western blot, flow cytometry, and caspase 3/7 activity assays were used to evaluate the induction of apoptosis/autophagy and/or necroptotic cell death. Cellular and mitochondrial reactive oxygen species (ROS) production was measured using CellROX and MitoSOX. Inhibitors/shRNA–targeting ROS, JNK and RIP1 kinase (RIPK1) were used to investigate the mechanism of cell killing. The synergistic interaction between oHSV and bortezomib was calculated using a Chou–Talalay analysis. NK cells isolated from normal human blood were co-cultured with tumor cells to evaluate cellular interactions. Q-PCR, ELISA, and FACS analysis were used to evaluate NK cell activation. Intracranial tumor xenografts were used to evaluate antitumor efficacy. Results: Combination treatment with bortezomib- and oHSV-induced necroptotic cell death and increased the production of mitochondrial ROS and JNK phosphorylation. Inhibitors/shRNA of RIPK1 and JNK rescued synergistic cell killing. Combination treatment also significantly enhanced NK cell activation and adjuvant NK cell therapy of mice treated with bortezomib and oHSV improved antitumor efficacy. Conclusions: This study provides a significant rationale for triple combination therapy with bortezomib, oHSV, and NK cells to improve efficacy, in glioblastoma patients. Clin Cancer Res; 22(21); 5265–76. ©2016 AACR. See related commentary by Suryadevara et al., p. 5164

Purpose: Elevated lipogenesis regulated by sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor playing a central role in lipid metabolism, is a novel characteristic of glioblastoma (GBM). The aim of this study was to identify effective approaches to suppress GBM growth by inhibition of SREBP-1. As SREBP activation is negatively regulated by endoplasmic reticulum (ER) cholesterol, we sought to determine whether suppression of sterol O-acyltransferase (SOAT), a key enzyme converting ER cholesterol to cholesterol esters (CE) to store in lipid droplets (LDs), effectively suppressed SREBP-1 and blocked GBM growth. Experimental Design: The presence of LDs in glioma patient tumor tissues was analyzed using immunofluorescence, immunohistochemistry, and electronic microscopy. Western blotting and real-time PCR were performed to analyze protein levels and gene expression of GBM cells, respectively. Intracranial GBM xenografts were used to determine the effects of genetically silencing SOAT1 and SREBP-1 on tumor growth. Results: Our study unraveled that cholesterol esterification and LD formation are signature of GBM, and human patients with glioma possess elevated LDs that correlate with GBM progression and poor survival. We revealed that SOAT1 is highly expressed in GBM and functions as a key player in controlling the cholesterol esterification and storage in GBM. Targeting SOAT1 suppresses GBM growth and prolongs survival in xenograft models via inhibition of SREBP-1–regulated lipid synthesis. Conclusions: Cholesterol esterification and storage in LDs are novel characteristics of GBM, and inhibiting SOAT1 to block cholesterol esterification is a promising therapeutic strategy to treat GBM by suppressing SREBP-1. Clin Cancer Res; 22(21); 5337–48. ©2016 AACR.

Background: To assess the benefits and harms of measures designed to reduce house dust mite (HDM) exposure in the management of house dust mite–sensitive allergic rhinitis. Methods: Systematic review of randomized controlled trials was made, in which HDM control measures have been evaluated in comparison with placebo or other HDM avoidance measures, in patients with clinically proven allergic rhinitis. Results: Nine trials involving 501 participants satisfied the inclusion criteria. These trials have investigated the effectiveness of bedroom environmental control programmes involving the use of HDM impermeable bedding covers (n = 4), acaricides (n = 2), high-efficiency particulate air filters (n = 2) and, using a factorial design, acaricide and HDM impermeable bedding covers in isolation and combination (n = 1). Seven of the nine trials reported that, when compared with control, the interventions studied resulted in significant reductions in HDM load. Of the interventions studied to date, acaricides appear to be the most promising, although the findings from these studies need to be interpreted with care because of their methodological limitations. House dust mite impermeable bedding as an isolated intervention is unlikely to offer benefit. Conclusions: Trials have tended to be small and of poor methodological quality, making it difficult to offer any definitive recommendations. Interventions that achieve substantial reductions in HDM load may offer some benefit in reducing rhinitis symptoms. Isolated use of HDM impermeable bedding is unlikely to prove

In this paper, we reflect upon shame and humiliation as threats to personal and professional integrity and moral agency within contemporary health care. A personal narrative, written by a nurse about a particular shift in a British National Health Service Accident and Emergency Department, is provided as a case study. This is critically reflected and commented upon in dialogue with insights into the nature of shame and humiliation. It is suggested that Accident and Emergency is a locus that is latently prone to dynamics of shame and humiliation, a potential exacerbated within a culture subject to externally-determined time targets that are enforced by a top-down system of surveillance and management. The result is that nurses may lose their sense of professional competence and responsibility, moral agency, and integrity, to their own personal detriment, as well as to the detriment of patients with whom they work. Insofar as examining a small part of a whole may suggest insights into the operation and ethos of a very large system, this very particular case study narrative/reflection has some important implications and lessons for the wider organization and provision of health care in Britain and beyond.

Background Allergic rhinitis is the most common of the allergic diseases. Despite improved understanding of the pathophysiology of allergic rhinitis and advances in its pharmacological treatment, its prevalence has increased worldwide. For patients whose symptoms remain uncontrolled despite medical treatment, allergen injection immunotherapy is advised. An allergen-based treatment may reduce symptoms, the need for medication and modify the natural course of this disease. Objectives To evaluate the efficacy and safety of subcutaneous specific allergen immunotherapy, compared with placebo, for reducing symptoms and medication requirements in seasonal allergic rhinitis patients. Search strategy We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1 2006), MEDLINE (1950 to 2006), EMBASE (1974 to 2006), Pre-MEDLINE, KOREAMED, INDMED, LILACS, PAKMEDINET, Scisearch, mRCT and the National Research Register. The date of the last search was February 2006. Selection criteria All studies identified by the searches were assessed to identify randomised controlled trials involving participants with symptoms of seasonal allergic rhinitis and proven allergen sensitivity, treated with subcutaneous allergen specific immunotherapy or corresponding placebo. Data collection and analysis Two independent authors identified all studies reporting double-blind, placebo controlled randomised trials of specific immunotherapy in patients with seasonal allergic rhinitis due to tree, grass or weed pollens. Two authors independently performed quality assessment of studies. Data from identified studies were abstracted onto a standard extraction sheet and subsequently entered into RevMan 4.2.8. Analysis was performed using the Standardised Mean Difference (SMD) method and a random-effects model; P values < 0.05 were considered statistically significant. The primary outcome measures were symptom scores, medication use, quality of life and adverse events. Main results We retrieved 1111 publications of which 51 satisfied our inclusion criteria. In total there were 2871 participants (1645 active, 1226 placebo), each receiving on average 18 injections. Duration of immunotherapy varied from three days to three years. Symptom score data from 15 trials were suitable for meta-analysis and showed an overall reduction in the immunotherapy group (SMD -0.73 (95% CI -0.97 to -0.50, P < 0.00001)). Medication score data from 13 trials showed an overall reduction in the immunotherapy group (SMD of -0.57 (95% CI -0.82 to -0.33, p

Aim To ascertain the influence of images depicting different qualities of pain on unselected outpatient pain clinic consultations. Methods A resource of 64 colour images depicting different qualities of pain was given to patients in clinic waiting rooms, which they could take into consultations and use as a focus for discussion with clinicians. A questionnaire enquiring into the value of such images was completed at the end of each consultation separately and anonymously by clinicians and patients. The questionnaires carried identifiers that allowed pairing in the analysis, which was undertaken qualitatively and thematically. Results Forty-four percent (20/45) of Pain Clinics declaring an interest in taking part in the study returned 64/80 (80%) pairs of questionnaires. Eighty-six percent (54) of patients related their pain to at least one image during their consultation and 67% found discussion of the images facilitated dialogue. Eighty two percent of clinicians reported improved communication as a result of the images with 78% reporting degrees of greater understanding of patients' pain. The four main themes identified in analysis of questionnaire data included: a broadening of verbal dialogue; a sense of improved clinician-patient relationship; limitations of setting (time); a variety of practical benefits for future use. The most prominent effect was that the images appeared to encourage discussion of the affective elements of the pain experience. Conclusion The results suggest that introducing a focus of images of pain into unselected pain consultations can facilitate discussion and lead to more fruitful dialogue between patients and clinicians.

(2009). The To-day and To-morrow Series and the Popularization of Science: An Introduction. Interdisciplinary Science Reviews: Vol. 34, The To-day and To-morrow Series, pp. 3-8.