• Substituting angiotensin-(1-7) to prevent lung damage in SARSCoV2 infection?

      Peiro, C; Moncada, Salvador; Department of Pharmacology, School of Medicine, Universidad Autonoma de Madrid, Madrid, Spain (2020)
    • A Subtype of Olfactory Bulb Interneurons Is Required for Odor Detection and Discrimination Behaviors.

      Takahashi, H; Ogawa, Y; Yoshihara, S; Asahina, R; Kinoshita, M; Kitano, T; Kitsuki, M; Tatsumi, K; Okuda, M; Tatsumi, K; et al. (2016-08-03)
      Neural circuits that undergo reorganization by newborn interneurons in the olfactory bulb (OB) are necessary for odor detection and discrimination, olfactory memory, and innate olfactory responses, including predator avoidance and sexual behaviors. The OB possesses many interneurons, including various types of granule cells (GCs); however, the contribution that each type of interneuron makes to olfactory behavioral control remains unknown. Here, we investigated the in vivo functional role of oncofetal trophoblast glycoprotein 5T4, a regulator for dendritic arborization of 5T4-expressing GCs (5T4 GCs), the level of which is reduced in the OB of 5T4 knock-out (KO) mice. Electrophysiological recordings with acute OB slices indicated that external tufted cells (ETCs) can be divided into two types, bursting and nonbursting. Optogenetic stimulation of 5T4 GCs revealed their connection to both bursting and nonbursting ETCs, as well as to mitral cells (MCs). Interestingly, nonbursting ETCs received fewer inhibitory inputs from GCs in 5T4 KO mice than from those in wild-type (WT) mice, whereas bursting ETCs and MCs received similar inputs in both mice. Furthermore, 5T4 GCs received significantly fewer excitatory inputs in 5T4 KO mice. Remarkably, in olfactory behavior tests, 5T4 KO mice had higher odor detection thresholds than the WT, as well as defects in odor discrimination learning. Therefore, the loss of 5T4 attenuates inhibitory inputs from 5T4 GCs to nonbursting ETCs and excitatory inputs to 5T4 GCs, contributing to disturbances in olfactory behavior. Our novel findings suggest that, among the various types of OB interneurons, the 5T4 GC subtype is required for odor detection and discrimination behaviors.
    • Successful downstream application of the Paxgene Blood RNA system from small blood samples in paediatric patients for quantitative PCR analysis

      Carrol, Enitan D; Salway, Fiona; Pepper, Stuart D; Saunders, Emma K; Mankhambo, Limangeni A; Ollier, William E; Hart, C Anthony; Day, Phillip; Malawi-Liverpool-Wellcome Trust Clinical Research Programme, PO Box 30096, Blantyre, Malawi, Africa. edcarrol@liv.ac.uk (2007)
      BACKGROUND: The challenge of gene expression studies is to reliably quantify levels of transcripts, but this is hindered by a number of factors including sample availability, handling and storage. The PAXgene Blood RNA System includes a stabilizing additive in a plastic evacuated tube, but requires 2.5 mL blood, which makes routine implementation impractical for paediatric use.The aim of this study was to modify the PAXgene Blood RNA System kit protocol for application to small, sick children, without compromising RNA integrity, and subsequently to perform quantitative analysis of ICAM and interleukin-6 gene expression.Aliquots of 0.86 mL PAXgene reagent were put into microtubes and 0.3 mL whole blood added to maintain the same recommended proportions as in the PAXgene evacuated tube system. RNA quality was assessed using the Agilent BioAnalyser 2100 and an in-house TaqMan assay which measures GAPDH transcript integrity by determining 3' to 5' ratios. qPCR analysis was performed on an additional panel of 7 housekeeping genes. Three reference genes (HPRT1, YWHAZ and GAPDH) were identified using the GeNORM algorithm, which were subsequently used to normalising target gene expression levels. ICAM-1 and IL-6 gene expression were measured in 87 Malawian children with invasive pneumococcal disease. RESULTS: Total RNA yield was between 1,114 and 2,950 ng and the BioAnalyser 2100 demonstrated discernible 18s and 28s bands. The cycle threshold values obtained for the seven housekeeping genes were between 15 and 30 and showed good consistency. Median relative ICAM and IL-6 gene expression were significantly reduced in non-survivors compared to survivors (ICAM: 3.56 vs 4.41, p = 0.04, and IL-6: 2.16 vs 6.73, p = 0.02). CONCLUSION: We have successfully modified the PAXgene blood collection system for use in small children and demonstrated preservation of RNA integrity and successful quantitative real-time PCR analysis.
    • Successive addition of electrons to sodium quinizarin-2- and -6-sulphonate in aqueous solution. a pulse and -radiolysis study

      Mukherjee, Tulsi; Land, Edward J; Swallow, A John; Guyan, P M; Bruce, J M (1988)
      Absorption characteristics of the semiquinone free radicals formed by one-electron reduction of quinizarin 2- and 6-sulphonates (Q2S and Q6S, respectively) have been studied. Second-order rate constants have been determined for the reactions of e, CO, H˙ and O with the two quinones and also for the reaction of the semiquinones with O2 and with themselves. The one-electron reduction potentials (vs. NHE) are E=–270 mV for Q2S and –249 mV for Q6S. They vary with pH in accordance with the pKa values of the parent and the semiquinone. The radicals are stable within the pH range 5–11. The stability constant is highest at pH 8.5, viz. ca. 1.45 for Q2S and 0.95 for Q6S. The one-electron reduction potentials of the semiquinones and the two electron reduction potentials of the quinones can be calculated to be E=–246 mV for Q2S and –213 mV for Q6S, and E=–258 mV for Q2S and –231 mV for Q6S. The variation of these quantities with pH has been related to pKa values for the relevant species. Properties of the radiolytically prepared fully reduced Q2S and Q6S are reported. Their acid forms are stable to oxygen. Adjustment to alkaline pH results in a loss of the sulphonate group from fully reduced Q2S but not from fully reduced Q6S. Reasons are given.
    • Sudan Black B, the specific histochemical stain for lipofuscin: a novel method to detect senescent cells.

      Evangelou, K; Gorgoulis, Vassilis G; Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Athens, 11527, Greece (2017)
      The Sudan-Black-B (SBB) histochemical stain is well known to specifically react against lipofuscin, an aggregate of oxidized proteins, lipids, and metals. Lipofuscin is related to many ageing processes. It is also known to accumulate in senescent cells. We recently proved that lipofuscin detection, when applying the SBB staining, is highly specific for the visualization of senescent cells. Here, we present in detail this SBB method that can detect senescent cells in any material, irrespective of its preparation. This provides unique advantages not only in understanding physiological processes and the pathophysiology of various diseases but also in estimating the response to therapeutic interventions.
    • The suitability of carboplatin solutions for 14-day continuous infusion by ambulatory pump: an HPLC-dynamic FAB study.

      Hadfield, John A; McGown, Alan T; Dawson, Martin J; Thatcher, Nick; Fox, Brian W; CRC Department of Experimental Chemotherapy, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK. (1993-08)
      The stability of aqueous carboplatin solutions over 14 days has been studied at 37 and 60 degrees C. High-performance liquid chromatography and dynamic FAB mass spectrometry studies have shown that carboplatin solutions were stable at 37 degrees C but degraded at 60 degrees C. Fluid loss through evaporation was significant at the higher temperature.
    • Suitability of cisplatin solutions for 14-day continuous infusion by ambulatory pump.

      Hrubisko, M; McGown, Alan T; Prendiville, Joseph A; Radford, John A; Thatcher, Nick; Fox, Brian W; Cancer Research Institute, Slovak Academy of Sciences, Bratislava. (1992)
      The stability of cisplatin (DDP) solutions (1 and 1.6 mg/ml in saline-mannitol) in plastic infusion bags was studied for up to 14 days at 25 degrees C, 37 degrees C and 60 degrees C. Small changes in the solution were observed, but no evidence of any decomposition product was seen. Some precipitation of DDP was seen in the 1.6-mg/ml solution at the lower temperatures. Fluid loss from the bags was significant at the higher temperatures.
    • Sulphated proteoglycan is required for collecting duct growth and branching but not nephron formation during kidney development.

      Davies, J; Lyon, Malcolm; Gallagher, John T; Garrod, D; Cancer Research Campaign Epithelial Morphogenesis Research Group, School of Biological Sciences, University of Manchester, UK. (1995-05)
      Kidney epithelia have separate origins; collecting ducts develop by ureteric bud growth and arborisation, nephrons by induced mesenchyme-epithelium transition. Both express sulphated glycosaminoglycans (GAGs) which are strikingly upregulated during nephron differentiation. However, sodium chlorate, an inhibitor of GAG sulphation, and the GAG-degrading enzymes heparitinase plus chondroitinase, did not prevent nephron development. In contrast, ureteric bud growth and branching were reversibly inhibited by the above reagents, the inhibition correlating quantitatively with sulphated GAG deprivation caused by a range of chlorate concentrations. Growth and branching could be independently restored during GAG deprivation by hepatocyte growth factor and phorbol-12-myristate acetate (PMA) respectively. Together these signalling effectors stimulated both branch initiation and growth. Thus growth and morphogenesis of ureteric bud involve distinct signalling pathways both regulated by GAGs.
    • Sulphonium salt formation from the reaction of methionine with some aziridine alkylating agents.

      Capps, Philip A; Jones, Alan R; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester M20 9BX, UK (1974)
    • SUMOylation of the GTPase Rac1 is required for optimal cell migration.

      Castillo-Lluva, Sonia; Tatham, M H; Jones, R C; Jaffray, E G; Edmondson, R D; Hay, R T; Malliri, Angeliki; Cell Signalling Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester, Manchester, M20 4BX, UK. (2010-11)
      The Rho-like GTPase, Rac1, induces cytoskeletal rearrangements required for cell migration. Rac activation is regulated through a number of mechanisms, including control of nucleotide exchange and hydrolysis, regulation of subcellular localization or modulation of protein-expression levels. Here, we identify that the small ubiquitin-like modifier (SUMO) E3-ligase, PIAS3, interacts with Rac1 and is required for increased Rac activation and optimal cell migration in response to hepatocyte growth factor (HGF) signalling. We demonstrate that Rac1 can be conjugated to SUMO-1 in response to hepatocyte growth factor treatment and that SUMOylation is enhanced by PIAS3. Furthermore, we identify non-consensus sites within the polybasic region of Rac1 as the main location for SUMO conjugation. We demonstrate that PIAS3-mediated SUMOylation of Rac1 controls the levels of Rac1-GTP and the ability of Rac1 to stimulate lamellipodia, cell migration and invasion. The finding that a Ras superfamily member can be SUMOylated provides an insight into the regulation of these critical mediators of cell behaviour. Our data reveal a role for SUMO in the regulation of cell migration and invasion.
    • Sun protection behavior after diagnosis of high-risk primary melanoma and risk of a subsequent primary

      von Schuckmann, L; Wilson, L; Hughes, M; Beesley, L; Janda, M; van der Pols, J; Smithers, B; Khosrotehrani, K; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia (2019)
      BACKGROUND: Melanoma survivors are at high risk of further primary melanomas. OBJECTIVE: To assess sun behavior after melanoma diagnosis and in relation to further primary melanomas. METHODS: We applied repeated measures latent class analysis to reported primary prevention behavior at time of diagnosis and every 6 months for 2 years after diagnosis in patients with clinical stage IB or II melanoma. Correlates of behavior trajectories and risk of subsequent primaries were determined by using multivariable logistic and Cox regression analyses, respectively. RESULTS: Among the 448 male and 341 female patients, sunscreen use fell into 3 trajectories: stable never-use (26% of males and 12% of females), stable sometimes-use (35% of males and 29% of females), and increased to often-use (39% of males and 59% of females). Most reduced their weekend sun exposure, but in 82% of males and 69% of females it remained increased. Males, smokers, the less educated, those who tanned, and those not self-checking their skin were more likely to have trajectories of inadequate protection. Patients with a history of melanoma before the study doubled their risk of another primary melanoma in the next 2 years if sunscreen use in that time was inadequate (hazard ratio, 2.45; 95% confidence interval, 1.00-6.06). LIMITATIONS: Patient-reported data are susceptible to recall bias. CONCLUSION: Our results may assist clinicians in identifying patients not using adequate sun protection and providing information for patient counseling.
    • Sunglasses to hide behind may also prevent melanoma of the eyes

      Dhomen, Nathalie; Mundra, Piyushkumar A; Marais, Richard; Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG (2021)
      In 1967, Sandy Posey pronounced that sunglasses are essential beachwear ( https://www.youtube.com/watch?v=4HVBEb-GA1Y ). Now, whole-genome sequencing reveals that ultraviolet radiation (UVR) can contribute to melanomas in the iris and conjunctiva, data that provide a molecular explanation for why it is important to protect our eyes from exposure to UVR.
    • Sunitinib in metastatic renal cell carcinoma patients with brain metastases.

      Gore, M E; Hariharan, S; Porta, C; Bracarda, S; Hawkins, Robert E; Bjarnason, G A; Oudard, S; Lee, S H; Carteni, G; Nieto, A; et al. (2011-02-01)
      In a broad patient population with metastatic renal cell carcinoma (RCC), enrolled in an open-label, expanded access program (EAP), the safety profile of sunitinib was manageable, and efficacy results were encouraging. Here, the authors report results for patients with baseline brain metastases participating in this global EAP.
    • Sunscreen photoprotection and vitamin D status

      Passeron, T; Bouillon, R; Callender, V; Cestari, T; Diepgen, TL; Green, Adèle C; van der Pols, JC; Bernard, BA; Ly, F; Bernerd, F; et al. (2019)
      BACKGROUND: Global concern about vitamin D deficiency has fuelled debates on photoprotection and the importance of solar exposure to meet vitamin D requirements. OBJECTIVES: To review the published evidence to reach a consensus on the influence of photoprotection by sunscreens on vitamin D status, considering other relevant factors. METHODS: An international panel of 13 experts in endocrinology, dermatology, photobiology, epidemiology and biological anthropology reviewed the literature prior to a 1-day meeting in June 2017, during which the evidence was discussed. Methods of assessment and determining factors of vitamin D status, and public health perspectives were examined and consequences of sun exposure and the effects of photoprotection were assessed. RESULTS: A serum level of >/= 50 nmol L(-1) 25(OH)D is a target for all individuals. Broad-spectrum sunscreens that prevent erythema are unlikely to compromise vitamin D status in healthy populations. Vitamin D screening should be restricted to those at risk of hypovitaminosis, such as patients with photosensitivity disorders, who require rigorous photoprotection. Screening and supplementation are advised for this group. CONCLUSIONS: Sunscreen use for daily and recreational photoprotection does not compromise vitamin D synthesis, even when applied under optimal conditions.
    • Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer

      Watt, Matthew J; Clark, Ashlee K; Selth, Luke A; Haynes, Vanessa R; Lister, Natalie; Rebello, Richard; Porter, Laura H; Niranjan, Birunthi; Whitby, Sarah T; Lo, Jennifer; et al. (2019)
      Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease. Deleting Cd36 in the prostate of cancer-susceptible Pten(-/-) mice reduced fatty acid uptake and the abundance of oncogenic signaling lipids and slowed cancer progression. Moreover, CD36 antibody therapy reduced cancer severity in patient-derived xenografts. We further demonstrated cross-talk between fatty acid uptake and de novo lipogenesis and found that dual targeting of these pathways more potently inhibited proliferation of human cancer-derived organoids compared to the single treatments. These findings identify a critical role for CD36-mediated fatty acid uptake in prostate cancer and suggest that targeting fatty acid uptake might be an effective strategy for treating prostate cancer.
    • Suppression of apoptosis allows differentiation and development of a multipotent hemopoietic cell line in the absence of added growth factors.

      Fairbairn, Leslie J; Cowling, Graham J; Reipert, B M; Dexter, T Michael; Cancer Research Campaign Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital, Manchester, England. (1993-09-10)
      In the absence of growth factors, hemopoietic cells die rapidly by the process of apoptosis. Transfection of the human bcl-2 gene into an interleukin-3 (IL-3)-dependent, multipotent hemopoietic cell line allowed these cells to survive in the absence of IL-3, both in serum-containing and serum-deprived conditions, and this survival was accompanied by multilineage differentiation. Moreover, single cell experiments showed that differentiation could occur in the absence of cell division. While these data do not rule out the possibility that growth factors can influence the lineage choice of multipotent cells, they suggest that exposure to growth factors may not be obligatory for the differentiation of stem cells. The data also support the hypothesis that differentiation is intrinsically determined and that the role of the hemopoietic growth factors is enabling rather than inductive.
    • Suppression of the Schizosaccharomyces pombe cut12.1 cell-cycle defect by mutations in cdc25 and genes involved in transcriptional and translational control.

      Tallada, Victor A; Bridge, Alan J; Emery, Patrick A; Hagan, Iain M; CRUK Cell Division Group, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom. (2007-05)
      Cdc25 phosphatase primes entry to mitosis by removing the inhibitory phosphate that is transferred to mitosis promoting factor (MPF) by Wee1 related kinases. A positive feedback loop then boosts Cdc25 and represses Wee1 activities to drive full-scale MPF activation and commitment to mitosis. Dominant mutations in the Schizosaccharomyces pombe spindle pole body (SPB) component Cut12 enable cdc25.22 mutants to overcome a G2 arrest at 36 degrees and enter mitosis. The recessive temperature-sensitive cut12.1 mutation results in the formation of monopolar spindles in which the spindle pole marker Sad1 is enriched on the nonfunctional SPB at 36 degrees . We identified mutations at five loci that suppressed the lethality of the recessive cut12.1 mutation at 36 degrees and conferred lethality at 20 degrees . Three of the five mutations led to the formation of monopolar spindles at restrictive temperatures, affected cell size at commitment to mitosis, and generated multiple Sad1 foci at nuclear periphery. The five loci, tfb2.rt1, tfb5.rt5, pla1.rt3, rpl4301.rt4, and rot2.1, and multicopy suppressors, including tfb1(+) and dbp10(+), are involved in transcription, translation, or RNA processing, prompting us to establish that elevating Cdc25 levels with the dominant cdc25.d1 allele, suppressed cut12.1. Thus, rot mutants provide a further link between protein production and cell-cycle progression.
    • Suppression of tumorigenicity in Ras-transformed fibroblasts by alpha 2(I) collagen.

      Travers, H; French, Neil S; Norton, John D; Cancer Research Campaign, Department of Gene Regulation, Paterson Institute for Cancer Research, Christie Hospital National Health Service Trust, Manchester, United Kingdom. (1996-10)
      Transformed fibroblasts exhibit reduced adhesion to substrata, a characteristic attributable in part to reduced expression/increased degradation of extracellular matrix (EM) proteins such as type I collagen. To directly assess the role of EM proteins in cellular transformation, a vKRas-transformed mouse fibroblast cell line was transfected with an alpha 2(I) collagen expression construct. Stable transfectants displaying a partial restoration of type I collagen expression showed a flatter morphology with increased adherence to the substratum. These clones also exhibited a reduced ability to clone in soft agar, slower growth kinetics, and suppression of tumorigenicity in nude mice. Restoration of type I collagen is correlated with down-regulation of ras oncogene-responsive NVL3 VL30 gene expression. These results suggest that in addition to suppressing tumorigenicity by promoting cellular adhesion and cytoskeletal organization, EM proteins such as type I collagen may also act to subvert oncoprotein signaling pathways associated with the malignant phenotype.
    • Suppressor cell activity of lymphocytes infiltrating human lung and breast tumours.

      Vose, Brent M; Moore, Michael; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1979-11-15)
    • Suppressor role of activating transcription factor 2 (ATF2) in skin cancer.

      Bhoumik, Anindita; Fichtman, Boris; Derossi, Charles; Breitwieser, Wolfgang; Kluger, Harriet M; Davis, Sean; Subtil, Antonio; Meltzer, Paul; Krajewski, Stan; Jones, Nic; et al. (2008-02-05)
      Activating transcription factor 2 (ATF2) regulates transcription in response to stress and growth factor stimuli. Here, we use a mouse model in which ATF2 was selectively deleted in keratinocytes. Crossing the conditionally expressed ATF2 mutant with K14-Cre mice (K14.ATF2(f/f)) resulted in selective expression of mutant ATF2 within the basal layer of the epidermis. When subjected to a two-stage skin carcinogenesis protocol [7,12-dimethylbenz[a]anthracene/phorbol 12-tetradecanoate 13-acetate (DMBA/TPA)], K14.ATF2(f/f) mice showed significant increases in both the incidence and prevalence of papilloma development compared with the WT ATF2 mice. Consistent with these findings, keratinocytes of K14.ATF2(f/f) mice exhibit greater anchorage-independent growth compared with ATF2 WT keratinocytes. Papillomas of K14.ATF2(f/f) mice exhibit reduced expression of presenilin1, which is associated with enhanced beta-catenin and cyclin D1, and reduced Notch1 expression. Significantly, a reduction of nuclear ATF2 and increased beta-catenin expression were seen in samples of squamous and basal cell carcinoma, as opposed to normal skin. Our data reveal that loss of ATF2 transcriptional activity serves to promote skin tumor formation, thereby indicating a suppressor activity of ATF2 in skin tumor formation.