#roy lindquist

[q-u-4-blog]

Lavinia: A Symbol of Resilience in Art

[innaschutts]

My second year attending the event of Jump 44 LHG who set up the camp on Wollaton Park in honour of the 508th Parachute Infantry Regiment. The 'Red Devils' were based on Wollaton Park prior to their drop into Normandy on the 6th June 1944. A bit of history: “The 508th Parachute Infantry Regiment was activated during World War II on 20 October 1942 at Camp Blanding, Florida. Lieutenant Colonel Roy E. Lindquist formed the unit and remained its commander throughout the war. After extensive training and maneuvers the 508th embarked on 19 December 1943 in New York City, New York and sailed on 28 December 1943 for Belfast, Northern Ireland, arriving there on 8 January 1944. After additional training at Cromore Estate in Portstewart, the regiment was moved by ship to Glasgow in Scotland and by train on 13 March 1944 to Wollaton Park in Nottinghamshire, England, where they became part of the veteran 82nd "All American" Airborne Division”- Wikipedia source. ——————————————————- #wollatonhall #508pir #reddevils #nottingham #nottinghamshire #itsinnottingham #ig_shotz #usa #exploretheworld #ig_uk #ischuttsphotography #visituk #ig_travel #visitnottinghamshire #ig_nottingham #visitnottingham #world_shotz #photosofengland #capturingbritain #ig_england #loves_united_kingdom #greatshotz #uk_greatshots #igersengland #explore_britain (at Wollaton Hall and Deer Park) https://www.instagram.com/p/BxGRjvxFoZs/?utm_source=ig_tumblr_share&igshid=iql8t9edejwo

[juudgeblog]

Morning Docket: 01.03.18

* Roy Moore’s lawyer — you know, Richard Jaffe, the Jewish one — is a “passionate supporter” of Senator-elect Doug Jones, and raised and donated money for his Senate campaign before voting for him in the Alabama special election. [Washington Examiner]

* Eversheds Sutherland celebrated the new year by announcing a merger with a Dutch affiliate firm, composed of eight partners and 32 lawyers across two offices. It’ll be known as Eversheds Sutherland Netherlands once the acquisition is complete. [American Lawyer]

* Speaking of mergers, Ballard Spahr celebrated the new year by completing its combination with Lindquist & Vennum. Ballard Spahr will retain its name, and the new firm will have 650 lawyers across 15 offices in the U.S. [Big Law Business]

* The former head of alumni relations for Chicago’s John Marshall Law claims in a new lawsuit that he was fired due to the school’s bias against older male employees. He alleges that Dean Darby Dickerson is trying to “eliminate the employment of men, and particularly older men.” [Law360 (sub. req.)]

* “If you’re too busy to follow this advice, you should follow this advice.” Try this New Year’s resolution on for size: take better care of yourself with these stress management tips. [Law.com] Morning Docket: 01.03.18 syndicated from http://ift.tt/2vKNZDn

[ijprspharmajobs-blog]

Heat Shock Proteins, a short review

INTRODUCTION Stressful conditions trigger certain defence mechanisms, including those at molecular levels. This was first seen in Drosophilia and was reported in 1974.1 Heat Shock Proteins (HSPs), also known as Stress-induced Proteins or Stress Proteins, are one such class of proteins that are produced in the body in response to stress, under the control of Heat Shock Factors (HSFs), although some are constitutively expressed. The stress may be heat, cold, UV radiation, infections, inflammation, heavy metal exposure or else. HSPs are produced by all organisms and are ubiquitously present. The primary involvement of these proteins is in the folding and stabilization of other proteins, and thus they play an intimate role in the aggregation of various other proteins.2 Besides action on protein folding, these HSPs also possess pro- and anti-apoptotic properties, making them suitable targets for drug development. The HSP families are classified according to their molecular weight.3 Table 1 describes in brief the classification as well as a few functions of these proteins. In the recent past, various drug have been developed which act in line or against the HSPs but a still in their infancy. Besides drugs, the HSPs are also employed as diagnostic tools in various cancers. These are referenced in Table 2. The flip side is the new set of adverse effects which are seen with these class of drugs. In patients with H.pylori infection which is implicated in the development of gastric carcinoma, it was observed that HSPs contributed to the progression of H. pylori-associated gastric carcinogenesis as well as led to the aggravation of gastric inflammation.33 Table 1: Functions of Heat Shock Proteins Family Function HSP90 (constitutive, induced)4 - 8 -          Regulatory interactions with signalling proteins -          Protein synthesis, folding and degradation -          Stabilization of misfolded proteins -          Binding of estrogen, progesterone, androgen, and aldosterone 5 -          Delivery of antigens to APCs 6 -          Cancer cells: enhances growth, supresses senescence, provides resistance to stress induced apoptosis. 7   -          Cardioprotective: binds to NO synthase and Guanylate cyclase, cause vascular relaxation  8 HSP70 (constitutive) 6, 9 - 12 -          Protein folding, membrane transport of proteins 9 -          Anti-apoptotic 10 -          Delivery of antigens to APCs 6 -          In sympathetic neurons: 11 •      HSP 72 – inhibits degradation of Tau protein, heat shock inducible •      HSC 70 - promotes degradation of Tau protein Low levels – associated with insulin resistance 12 HSP60 (constitutive) -          In the mitochondria, replication and transcription of DNA, pro-survival. 13 -          In the cytosol, complexes and inhibits maturation and activation of Caspase 3 – Anti apoptotic 14 -          At the surface and extracellularly, stimulates immune response 15 HSP40 -          Protein folding, co-chaperon for HSP70 16 -          HSP40-70 complex – modulate accumulation of polyglutamine proteins 17 HSP27 (β1) (induced) -          Anti-apoptotic, prevents proteolysis by inhibiting liberation of cytochrome c from mitochondria18 Small HSPs -          Stabilization of misfolded proteins19 Table 2: Drugs acting via HSPs Family Drug Disease Against HSP90 Geldanamycin (derivative, 17-allylamine,17-demethoxigeldanamycin) Malaria20 Huntington’s disease21 Cacncers22,23 Efungumab Invasive Candidiasis24 Against HSP70 Triptolide Pancreatic cancer25 Mesothelioma26 Methylene blue (inhibits ATPase activity of HSP72) Alzheimer’s disease27 Pro-HSP60 Bortezomib28 Malignancies, increases expression of HSP60 on malignant cells and thus enhances immune response against tumour cells Against HSP40 Quercetin (inhibits HSP 40 and 27) Parkinson’s disease29 Cancer30 Against HSP27 Apatorsen (antisense oligonucleotide) Cancer31 Diagnostic tool32 Increased levels - Renal injury and fibrosis, Cancers of breast, lung, liver, prostate, rectal, osteosarcoma, leukaemia, cerebral and cardiac ischemia Reduced levels – oesophageal cancer Anti-HSP27 IgA – Gynaecological malignancies Against HSP70 Triptolide Pancreatic cancer25 Mesothelioma26 Methylene blue (inhibits ATPase activity of HSP72) Alzheimer’s disease27 Pro-HSP60 Bortezomib28 Malignancies, increases expression of HSP60 on malignant cells and thus enhances immune response against tumour cells Against HSP40 Quercetin (inhibits HSP 40 and 27) Parkinson’s disease29 Cancer30 Against HSP27 Apatorsen (antisense oligonucleotide) Cancer31 Diagnostic tool32 Increased levels - Renal injury and fibrosis, Cancers of breast, lung, liver, prostate, rectal, osteosarcoma, leukaemia, cerebral and cardiac ischemia Reduced levels – oesophageal cancer Anti-HSP27 IgA – Gynaecological malignancies   Autoimmune disease: Since these are highly conserved in nature, they are the initiators as well as the targets of autoimmune attack. Molecular mimicry and cross presentation of antigens are the phenomena of their involvement in autoimmunity. Their roles have been implicated in atherosclerosis, uveitis, lupus and Behcet’s disease. 34 Atherosclerosis: Risk factors for atherosclerosis including infection, oxidative stress, biomechanical stress, all lead to the overproduction of HSPs through the activation of heat shock transcription factor 1 which may lead to worsening of atherosclerosis.35 The anti-apoptotic property may lead to a poor prognosis and resistance to therapy in cancer which the anti-apoptotic activity may be therapeutically advantageous.36 Insomnia or sleep deprivation can lead to an increased level of HSPs acting as a neuroprotective response, emphasizing on the role of adequate sleep in disease prevention.37 CONCLUSION Harms and benefits are two sides of the same coin, as is the case with heat shock proteins. Despite their presence ubiquitously, a small rise or fall in their levels can have a different specific new set of adverse implications. However, despite the availability of information, further research in needed in order to develop newer drugs which may prove beneficial in the treatment of difficult, incurable diseases. REFERENCES Schlesinger, M. J. (1990). Heat shock proteins. The Journal of Biological Chemistry, 265(21), 12111–12114. PMid:2197269 Lindquist, S., & Craig, E. A. (1988). The heat-shock proteins. Annual review of genetics, 22(1), 631-677. https://doi.org/10.1146/annurev.ge.22.120188.003215, PMid:2853609 Wirth, D., Gustin, P., Drion, P., Dessy-Doize, C., & Christians, E. S. (2002). Heat shock proteins. I: Classification and roles in pathological processes. In Annales de Médecine Vétérinaire (Vol. 146, No. 4, pp. 201-216). Annales Medecine Veterinaire. Jackson, S. E. (2012). Hsp90: structure and function. In Molecular chaperones(pp. 155-240). Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2012_356, PMid:22955504 Joab, I., Radanyi, C., Renoir, M., Buchou, T., Catelli, M. G., Binart, N., ... & Baulieu, E. E. (1984). Common non-hormone binding component in non-transformed chick oviduct receptors of four steroid hormones. Nature, 308(5962), 850. https://doi.org/10.1038/308850a0, PMid:6201744 Gaston, J. S. H. (2002). Heat Shock Proteins and Innate immunity. Clin Exp Immunol, 127(1), 1–3. https://doi.org/10.1046/j.1365-2249.2002.01759.x, https://doi.org/10.1111/j.1365-2249.1990.tb05394.x, PMid:11882025, PMCid:PMC1906278 Workman, P., Burrows, F., Neckers, L., & Rosen, N. (2007). Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci, 1113, 202–216. https://doi.org/10.1196/annals.1391.012, PMid:17513464 Antonova, G., Lichtenbeld, H., Xia, T., Chatterjee, A., Dimitropoulou, C., & Catravas J. D. (2007). Functional significance of hsp90 complexes with NOS and sGC in endothelial cells. Clin Hemorheol Microcirc, 37(1-2), 19-35. Hartl, F.U. (1996). Molecular chaperones in cellular protein folding. Nature, 381, 571-579. https://doi.org/10.1038/381571a0, PMid:8637592 Gehrmann, M., Radons, J., Molls, M., & Multhoff, G. (2008). The therapeutic implications of clinically applied modifiers of heat shock protein 70 (Hsp70) expression by tumor cells. Cell Stress Chaperones, 13(1), 1-10. https://doi.org/10.1007/s12192-007-0006-0, PMid:18347936, PMCid:PMC2666213 Jinwal, U. K., Akoury, E., Abisambra, J. F., O'Leary, J. C., Thompson, A.D., Blair, L. J., et al. (2013). Imbalance of Hsp70 family variants fosters tau accumulation. FASEB J, 27(4), 1450-1459. https://doi.org/10.1096/fj.12-220889, PMid:23271055, PMCid:PMC3606536 Chichester, L., Wylie, A. T., Craft, S., & Kavanagh, K. (2015). Muscle heat shock protein 70 predicts insulin resistance with aging. J Gerontol A Biol Sci Med Sci, 70(2), 155-62. https://doi.org/10.1093/gerona/glu015, PMid:24532784, PMCid:PMC4311181 Kaufman, B. A., Kolesar, J. E., Perlman, P. S., & Butow, R. A. (2003). A function for the mitochondrial chaperonin Hsp60 in the structure and transmission of mitochondrial DNA nucleoids in Saccharomyces cerevisiae. J Cell Biol, 163, 457-461. https://doi.org/10.1083/jcb.200306132, PMid:14597775, PMCid:PMC2173642 Xanthoudakis, S., Roy, S., Rasper, D., Hennessey, T., Aubin, Y., Cassady, R., et al. (1999). Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis. EMBO J, 18(18), 2049-2056. https://doi.org/10.1093/emboj/18.8.2049, PMid:10205159, PMCid:PMC1171289 Pockley, A. G., Muthana, M., & Calderwood, S. K. (2008). The dual immunoregulatory roles of stress proteins. Trends Biochem Sci, 33, 71-79. https://doi.org/10.1016/j.tibs.2007.10.005, PMid:18182297 Castanie-Cornet, M. P., Bruel, N., & Genevaux, P. (2014). Chaperone networking facilitates protein targeting to the bacterial cytoplasmic membrane. Biochim Biophys. Acta, 1843, 1442-1456. https://doi.org/10.1016/j.bbamcr.2013.11.007, PMid:24269840 Wacker, J. L., Zareie, M. H., Fong, H., Sarikaya, M., & Muchowski, P. J. (2004). Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nature Structural & Molecular Biology, 11(12), 1215-1222. https://doi.org/10.1038/nsmb860, PMid:15543156 Paul, C., Manero, F., Gonin, S., Kretz-Remy, C., Virot, S., & Arrigo, A. P. (2002). Hsp27 as a negative regulator of cytochrome C release. Mol Cell Biol, 22(3):816-34. https://doi.org/10.1128/MCB.22.3.816-834.2002, PMid:11784858, PMCid:PMC133538 Ungelenk, S., Moayed, F., Ho, C. T., Grousl, T., Scharf, A., Mashaghi, A., et al. (2016). Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding. Nature Communications, 7, Article number: 13673. https://doi.org/10.1038/ncomms13673, PMid:27901028, PMCid:PMC5141385 Wang, T., Maser, P., & Picard, D. (2016). Inhibition of Plasmodium falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-carbazoles. Med. Chem., 59(13), 6344–6352. https://doi.org/10.1021/acs.jmedchem.6b00591, PMid:27312008 Sittler, A., Lurz, R., Lueder, G., Priller, J., Lehrach, H., Hayer-Hartl, M. K., et al. (2001). Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease. Human Molecular Genetics, 10(12), 1307-1315. https://doi.org/10.1093/hmg/10.12.1307, PMid:11406612 Jurczyszyn, A., Zebzda, A., Czepiel, J., Perucki, W., Bazan-Socha, S., Cibor, D., et al. (2014). Geldanamycin and Its Derivatives Inhibit the Growth of Myeloma Cells and Reduce the Expression of the MET Receptor. J Cancer, 5(6), 480–490. https://doi.org/10.7150/jca.8731, PMid:24959301, PMCid:PMC4066360 Li, Y., Zhang, T., & Sun, D. (2009). New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential. Drug Resist Updat, 12(1-2), 17–27. https://doi.org/10.1016/j.drup.2008.12.002, PMid:19179103, PMCid:PMC2692088 Karwa, R., & Wargo, K. A. (2009). Efungumab: a novel agent in the treatment of invasive candidiasis. Ann Pharmacother, 43(11), 1818-1823. https://doi.org/10.1345/aph.1M218, PMid:19773528 Phillips, P. A., Dudeja, V., McCarroll, J.A., Borja-Cacho, D., Dawra, R. K., Grizzle, W. E., et al. (2007). Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res, 67(19), 9407-9416. https://doi.org/10.1158/0008-5472.CAN-07-1077, PMid:17909050 Jacobson, B. A., Chen, E. Z., Tang, S., Belgum, H. S., McCauley, J. A., Evenson, K. A., et al. (2015). Triptolide and its prodrug minnelide suppress Hsp70 and inhibit in vivo growth in a xenograft model of mesothelioma. Genes Cancer, 6(3-4), 144–152. PMid:26000097, PMCid:PMC4426951 O'Leary, J. C., Li, Q., Marinec, P., Blair, L. J., Congdon, E. E., Johnson, A. G., et al. (2010). Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Molecular Neurodegeneration, 5(1), Article 45. https://doi.org/10.1186/1750-1326-5-45, PMid:21040568, PMCid:PMC2989315 Chang, C. L., Hsu, Y. T., Wu. C. C., Yang, Y. C., Wang, C., Wu, T. C., et al. (2012). Immune mechanism of the antitumor effects generated by bortezomib. J Immunol, 189(6), 3209-3220. https://doi.org/10.4049/jimmunol.1103826, PMid:22896634 Ekimov, I. V., & Plaksina, D. V. (2017). Effects of Quercetin on Neurodegenerative and Compensatory Processes in the Nigrostriatal System in a Model of the Preclinical Stage of Parkinson’s Disease in Rats. Neuroscience and Behavioral Physiology, 47(9), 1029–1036. https://doi.org/10.1007/s11055-017-0508-x McConnell, J. R., & McAlpine, S. R. (2013). Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets. Bioorg Med Chem Lett, 23(7), 1923–1928. https://doi.org/10.1016/j.bmcl.2013.02.014, PMid:23453837, PMCid:PMC3602338 Chi, K. N., Yu, E. Y., Jacobs, C., Bazov, J., Kollmannsberger, C., Higano, C.S., et al. (2016). A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers. Ann Oncol, 27(6), 1116-1122. https://doi.org/10.1093/annonc/mdw068, PMid:27022067 Vidyasagar, A., Wilson, N. A., & Djamali, A. (2012). Heat shock protein 27 (HSP27): biomarker of disease and therapeutic target. Fibrogenesis & Tissue Repair, 5(1), 7. https://doi.org/10.1186/1755-1536-5-7, PMid:22564335, PMCid:PMC3464729 Lee, H. J., Ock, C.Y., Kin, S. J., & Hahm, K. B. (2010). Heat Shock Protein: Hard Worker or Bad Offender for Gastric Diseases. International Journal of Proteomics, 2010, 1-11. https://doi.org/10.1155/2010/259163, PMid:22084675, PMCid:PMC3195352 Moudgil, K. D., Thompson, S. J., Geraci, F., Paepe, B. D., & Shoenfeld, Y. (2013). Heat-Shock Proteins in Autoimmunity. Autoimmune Diseases, 2013; 1-3. https://doi.org/10.1155/2013/621417 Xu, Q. (2002). Role of Heat Shock Proteins in Atherosclerosis. Atherosclerosis, Thrombosis and Vascular biology, 22, 1547-1559. https://doi.org/10.1161/01.ATV.0000029720.59649.50 Calderwood, S.K., & Gong, J. (2016). Heat Shock Proteins Promote Cancer: It's a Protection Racket. Trends in Biochemical Sciences, 41(4), 311-323. https://doi.org/10.1016/j.tibs.2016.01.003, PMid:26874923, PMCid:PMC4911230 Terao, A., Steininger, T. L., Hyder, K., Apte-Deshpande, A., Ding, J., Rishipathak, D., et al. (2003). Differential increase in the expression of heat shock protein family members during sleep deprivation and during sleep. Neuroscience, 116(1), 187-200. https://doi.org/10.1016/S0306-4522(02)00695-4 Read the full article

[ijprsteam-blog]

Heat Shock Proteins, a short review

INTRODUCTION Stressful conditions trigger certain defence mechanisms, including those at molecular levels. This was first seen in Drosophilia and was reported in 1974.1 Heat Shock Proteins (HSPs), also known as Stress-induced Proteins or Stress Proteins, are one such class of proteins that are produced in the body in response to stress, under the control of Heat Shock Factors (HSFs), although some are constitutively expressed. The stress may be heat, cold, UV radiation, infections, inflammation, heavy metal exposure or else. HSPs are produced by all organisms and are ubiquitously present. The primary involvement of these proteins is in the folding and stabilization of other proteins, and thus they play an intimate role in the aggregation of various other proteins.2 Besides action on protein folding, these HSPs also possess pro- and anti-apoptotic properties, making them suitable targets for drug development. The HSP families are classified according to their molecular weight.3 Table 1 describes in brief the classification as well as a few functions of these proteins. In the recent past, various drug have been developed which act in line or against the HSPs but a still in their infancy. Besides drugs, the HSPs are also employed as diagnostic tools in various cancers. These are referenced in Table 2. The flip side is the new set of adverse effects which are seen with these class of drugs. In patients with H.pylori infection which is implicated in the development of gastric carcinoma, it was observed that HSPs contributed to the progression of H. pylori-associated gastric carcinogenesis as well as led to the aggravation of gastric inflammation.33 Table 1: Functions of Heat Shock Proteins Family Function HSP90 (constitutive, induced)4 - 8 -          Regulatory interactions with signalling proteins -          Protein synthesis, folding and degradation -          Stabilization of misfolded proteins -          Binding of estrogen, progesterone, androgen, and aldosterone 5 -          Delivery of antigens to APCs 6 -          Cancer cells: enhances growth, supresses senescence, provides resistance to stress induced apoptosis. 7   -          Cardioprotective: binds to NO synthase and Guanylate cyclase, cause vascular relaxation  8 HSP70 (constitutive) 6, 9 - 12 -          Protein folding, membrane transport of proteins 9 -          Anti-apoptotic 10 -          Delivery of antigens to APCs 6 -          In sympathetic neurons: 11 •      HSP 72 – inhibits degradation of Tau protein, heat shock inducible •      HSC 70 - promotes degradation of Tau protein Low levels – associated with insulin resistance 12 HSP60 (constitutive) -          In the mitochondria, replication and transcription of DNA, pro-survival. 13 -          In the cytosol, complexes and inhibits maturation and activation of Caspase 3 – Anti apoptotic 14 -          At the surface and extracellularly, stimulates immune response 15 HSP40 -          Protein folding, co-chaperon for HSP70 16 -          HSP40-70 complex – modulate accumulation of polyglutamine proteins 17 HSP27 (β1) (induced) -          Anti-apoptotic, prevents proteolysis by inhibiting liberation of cytochrome c from mitochondria18 Small HSPs -          Stabilization of misfolded proteins19 Table 2: Drugs acting via HSPs Family Drug Disease Against HSP90 Geldanamycin (derivative, 17-allylamine,17-demethoxigeldanamycin) Malaria20 Huntington’s disease21 Cacncers22,23 Efungumab Invasive Candidiasis24 Against HSP70 Triptolide Pancreatic cancer25 Mesothelioma26 Methylene blue (inhibits ATPase activity of HSP72) Alzheimer’s disease27 Pro-HSP60 Bortezomib28 Malignancies, increases expression of HSP60 on malignant cells and thus enhances immune response against tumour cells Against HSP40 Quercetin (inhibits HSP 40 and 27) Parkinson’s disease29 Cancer30 Against HSP27 Apatorsen (antisense oligonucleotide) Cancer31 Diagnostic tool32 Increased levels - Renal injury and fibrosis, Cancers of breast, lung, liver, prostate, rectal, osteosarcoma, leukaemia, cerebral and cardiac ischemia Reduced levels – oesophageal cancer Anti-HSP27 IgA – Gynaecological malignancies Against HSP70 Triptolide Pancreatic cancer25 Mesothelioma26 Methylene blue (inhibits ATPase activity of HSP72) Alzheimer’s disease27 Pro-HSP60 Bortezomib28 Malignancies, increases expression of HSP60 on malignant cells and thus enhances immune response against tumour cells Against HSP40 Quercetin (inhibits HSP 40 and 27) Parkinson’s disease29 Cancer30 Against HSP27 Apatorsen (antisense oligonucleotide) Cancer31 Diagnostic tool32 Increased levels - Renal injury and fibrosis, Cancers of breast, lung, liver, prostate, rectal, osteosarcoma, leukaemia, cerebral and cardiac ischemia Reduced levels – oesophageal cancer Anti-HSP27 IgA – Gynaecological malignancies   Autoimmune disease: Since these are highly conserved in nature, they are the initiators as well as the targets of autoimmune attack. Molecular mimicry and cross presentation of antigens are the phenomena of their involvement in autoimmunity. Their roles have been implicated in atherosclerosis, uveitis, lupus and Behcet’s disease. 34 Atherosclerosis: Risk factors for atherosclerosis including infection, oxidative stress, biomechanical stress, all lead to the overproduction of HSPs through the activation of heat shock transcription factor 1 which may lead to worsening of atherosclerosis.35 The anti-apoptotic property may lead to a poor prognosis and resistance to therapy in cancer which the anti-apoptotic activity may be therapeutically advantageous.36 Insomnia or sleep deprivation can lead to an increased level of HSPs acting as a neuroprotective response, emphasizing on the role of adequate sleep in disease prevention.37 CONCLUSION Harms and benefits are two sides of the same coin, as is the case with heat shock proteins. Despite their presence ubiquitously, a small rise or fall in their levels can have a different specific new set of adverse implications. However, despite the availability of information, further research in needed in order to develop newer drugs which may prove beneficial in the treatment of difficult, incurable diseases. REFERENCES Schlesinger, M. J. (1990). Heat shock proteins. The Journal of Biological Chemistry, 265(21), 12111–12114. PMid:2197269 Lindquist, S., & Craig, E. A. (1988). The heat-shock proteins. Annual review of genetics, 22(1), 631-677. https://doi.org/10.1146/annurev.ge.22.120188.003215, PMid:2853609 Wirth, D., Gustin, P., Drion, P., Dessy-Doize, C., & Christians, E. S. (2002). Heat shock proteins. I: Classification and roles in pathological processes. In Annales de Médecine Vétérinaire (Vol. 146, No. 4, pp. 201-216). Annales Medecine Veterinaire. Jackson, S. E. (2012). Hsp90: structure and function. In Molecular chaperones(pp. 155-240). Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2012_356, PMid:22955504 Joab, I., Radanyi, C., Renoir, M., Buchou, T., Catelli, M. G., Binart, N., ... & Baulieu, E. E. (1984). Common non-hormone binding component in non-transformed chick oviduct receptors of four steroid hormones. Nature, 308(5962), 850. https://doi.org/10.1038/308850a0, PMid:6201744 Gaston, J. S. H. (2002). Heat Shock Proteins and Innate immunity. Clin Exp Immunol, 127(1), 1–3. https://doi.org/10.1046/j.1365-2249.2002.01759.x, https://doi.org/10.1111/j.1365-2249.1990.tb05394.x, PMid:11882025, PMCid:PMC1906278 Workman, P., Burrows, F., Neckers, L., & Rosen, N. (2007). Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci, 1113, 202–216. https://doi.org/10.1196/annals.1391.012, PMid:17513464 Antonova, G., Lichtenbeld, H., Xia, T., Chatterjee, A., Dimitropoulou, C., & Catravas J. D. (2007). Functional significance of hsp90 complexes with NOS and sGC in endothelial cells. Clin Hemorheol Microcirc, 37(1-2), 19-35. Hartl, F.U. (1996). Molecular chaperones in cellular protein folding. Nature, 381, 571-579. https://doi.org/10.1038/381571a0, PMid:8637592 Gehrmann, M., Radons, J., Molls, M., & Multhoff, G. (2008). The therapeutic implications of clinically applied modifiers of heat shock protein 70 (Hsp70) expression by tumor cells. Cell Stress Chaperones, 13(1), 1-10. https://doi.org/10.1007/s12192-007-0006-0, PMid:18347936, PMCid:PMC2666213 Jinwal, U. K., Akoury, E., Abisambra, J. F., O'Leary, J. C., Thompson, A.D., Blair, L. J., et al. (2013). Imbalance of Hsp70 family variants fosters tau accumulation. FASEB J, 27(4), 1450-1459. https://doi.org/10.1096/fj.12-220889, PMid:23271055, PMCid:PMC3606536 Chichester, L., Wylie, A. T., Craft, S., & Kavanagh, K. (2015). Muscle heat shock protein 70 predicts insulin resistance with aging. J Gerontol A Biol Sci Med Sci, 70(2), 155-62. https://doi.org/10.1093/gerona/glu015, PMid:24532784, PMCid:PMC4311181 Kaufman, B. A., Kolesar, J. E., Perlman, P. S., & Butow, R. A. (2003). A function for the mitochondrial chaperonin Hsp60 in the structure and transmission of mitochondrial DNA nucleoids in Saccharomyces cerevisiae. J Cell Biol, 163, 457-461. https://doi.org/10.1083/jcb.200306132, PMid:14597775, PMCid:PMC2173642 Xanthoudakis, S., Roy, S., Rasper, D., Hennessey, T., Aubin, Y., Cassady, R., et al. (1999). Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis. EMBO J, 18(18), 2049-2056. https://doi.org/10.1093/emboj/18.8.2049, PMid:10205159, PMCid:PMC1171289 Pockley, A. G., Muthana, M., & Calderwood, S. K. (2008). The dual immunoregulatory roles of stress proteins. Trends Biochem Sci, 33, 71-79. https://doi.org/10.1016/j.tibs.2007.10.005, PMid:18182297 Castanie-Cornet, M. P., Bruel, N., & Genevaux, P. (2014). Chaperone networking facilitates protein targeting to the bacterial cytoplasmic membrane. Biochim Biophys. Acta, 1843, 1442-1456. https://doi.org/10.1016/j.bbamcr.2013.11.007, PMid:24269840 Wacker, J. L., Zareie, M. H., Fong, H., Sarikaya, M., & Muchowski, P. J. (2004). Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nature Structural & Molecular Biology, 11(12), 1215-1222. https://doi.org/10.1038/nsmb860, PMid:15543156 Paul, C., Manero, F., Gonin, S., Kretz-Remy, C., Virot, S., & Arrigo, A. P. (2002). Hsp27 as a negative regulator of cytochrome C release. Mol Cell Biol, 22(3):816-34. https://doi.org/10.1128/MCB.22.3.816-834.2002, PMid:11784858, PMCid:PMC133538 Ungelenk, S., Moayed, F., Ho, C. T., Grousl, T., Scharf, A., Mashaghi, A., et al. (2016). Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding. Nature Communications, 7, Article number: 13673. https://doi.org/10.1038/ncomms13673, PMid:27901028, PMCid:PMC5141385 Wang, T., Maser, P., & Picard, D. (2016). Inhibition of Plasmodium falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-carbazoles. Med. Chem., 59(13), 6344–6352. https://doi.org/10.1021/acs.jmedchem.6b00591, PMid:27312008 Sittler, A., Lurz, R., Lueder, G., Priller, J., Lehrach, H., Hayer-Hartl, M. K., et al. (2001). Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease. Human Molecular Genetics, 10(12), 1307-1315. https://doi.org/10.1093/hmg/10.12.1307, PMid:11406612 Jurczyszyn, A., Zebzda, A., Czepiel, J., Perucki, W., Bazan-Socha, S., Cibor, D., et al. (2014). Geldanamycin and Its Derivatives Inhibit the Growth of Myeloma Cells and Reduce the Expression of the MET Receptor. J Cancer, 5(6), 480–490. https://doi.org/10.7150/jca.8731, PMid:24959301, PMCid:PMC4066360 Li, Y., Zhang, T., & Sun, D. (2009). New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential. Drug Resist Updat, 12(1-2), 17–27. https://doi.org/10.1016/j.drup.2008.12.002, PMid:19179103, PMCid:PMC2692088 Karwa, R., & Wargo, K. A. (2009). Efungumab: a novel agent in the treatment of invasive candidiasis. Ann Pharmacother, 43(11), 1818-1823. https://doi.org/10.1345/aph.1M218, PMid:19773528 Phillips, P. A., Dudeja, V., McCarroll, J.A., Borja-Cacho, D., Dawra, R. K., Grizzle, W. E., et al. (2007). Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res, 67(19), 9407-9416. https://doi.org/10.1158/0008-5472.CAN-07-1077, PMid:17909050 Jacobson, B. A., Chen, E. Z., Tang, S., Belgum, H. S., McCauley, J. A., Evenson, K. A., et al. (2015). Triptolide and its prodrug minnelide suppress Hsp70 and inhibit in vivo growth in a xenograft model of mesothelioma. Genes Cancer, 6(3-4), 144–152. PMid:26000097, PMCid:PMC4426951 O'Leary, J. C., Li, Q., Marinec, P., Blair, L. J., Congdon, E. E., Johnson, A. G., et al. (2010). Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Molecular Neurodegeneration, 5(1), Article 45. https://doi.org/10.1186/1750-1326-5-45, PMid:21040568, PMCid:PMC2989315 Chang, C. L., Hsu, Y. T., Wu. C. C., Yang, Y. C., Wang, C., Wu, T. C., et al. (2012). Immune mechanism of the antitumor effects generated by bortezomib. J Immunol, 189(6), 3209-3220. https://doi.org/10.4049/jimmunol.1103826, PMid:22896634 Ekimov, I. V., & Plaksina, D. V. (2017). Effects of Quercetin on Neurodegenerative and Compensatory Processes in the Nigrostriatal System in a Model of the Preclinical Stage of Parkinson’s Disease in Rats. Neuroscience and Behavioral Physiology, 47(9), 1029–1036. https://doi.org/10.1007/s11055-017-0508-x McConnell, J. R., & McAlpine, S. R. (2013). Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets. Bioorg Med Chem Lett, 23(7), 1923–1928. https://doi.org/10.1016/j.bmcl.2013.02.014, PMid:23453837, PMCid:PMC3602338 Chi, K. N., Yu, E. Y., Jacobs, C., Bazov, J., Kollmannsberger, C., Higano, C.S., et al. (2016). A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers. Ann Oncol, 27(6), 1116-1122. https://doi.org/10.1093/annonc/mdw068, PMid:27022067 Vidyasagar, A., Wilson, N. A., & Djamali, A. (2012). Heat shock protein 27 (HSP27): biomarker of disease and therapeutic target. Fibrogenesis & Tissue Repair, 5(1), 7. https://doi.org/10.1186/1755-1536-5-7, PMid:22564335, PMCid:PMC3464729 Lee, H. J., Ock, C.Y., Kin, S. J., & Hahm, K. B. (2010). Heat Shock Protein: Hard Worker or Bad Offender for Gastric Diseases. International Journal of Proteomics, 2010, 1-11. https://doi.org/10.1155/2010/259163, PMid:22084675, PMCid:PMC3195352 Moudgil, K. D., Thompson, S. J., Geraci, F., Paepe, B. D., & Shoenfeld, Y. (2013). Heat-Shock Proteins in Autoimmunity. Autoimmune Diseases, 2013; 1-3. https://doi.org/10.1155/2013/621417 Xu, Q. (2002). Role of Heat Shock Proteins in Atherosclerosis. Atherosclerosis, Thrombosis and Vascular biology, 22, 1547-1559. https://doi.org/10.1161/01.ATV.0000029720.59649.50 Calderwood, S.K., & Gong, J. (2016). Heat Shock Proteins Promote Cancer: It's a Protection Racket. Trends in Biochemical Sciences, 41(4), 311-323. https://doi.org/10.1016/j.tibs.2016.01.003, PMid:26874923, PMCid:PMC4911230 Terao, A., Steininger, T. L., Hyder, K., Apte-Deshpande, A., Ding, J., Rishipathak, D., et al. (2003). Differential increase in the expression of heat shock protein family members during sleep deprivation and during sleep. Neuroscience, 116(1), 187-200. https://doi.org/10.1016/S0306-4522(02)00695-4 Read the full article

[ijprspharmanews-blog]

Heat Shock Proteins, a short review

INTRODUCTION Stressful conditions trigger certain defence mechanisms, including those at molecular levels. This was first seen in Drosophilia and was reported in 1974.1 Heat Shock Proteins (HSPs), also known as Stress-induced Proteins or Stress Proteins, are one such class of proteins that are produced in the body in response to stress, under the control of Heat Shock Factors (HSFs), although some are constitutively expressed. The stress may be heat, cold, UV radiation, infections, inflammation, heavy metal exposure or else. HSPs are produced by all organisms and are ubiquitously present. The primary involvement of these proteins is in the folding and stabilization of other proteins, and thus they play an intimate role in the aggregation of various other proteins.2 Besides action on protein folding, these HSPs also possess pro- and anti-apoptotic properties, making them suitable targets for drug development. The HSP families are classified according to their molecular weight.3 Table 1 describes in brief the classification as well as a few functions of these proteins. In the recent past, various drug have been developed which act in line or against the HSPs but a still in their infancy. Besides drugs, the HSPs are also employed as diagnostic tools in various cancers. These are referenced in Table 2. The flip side is the new set of adverse effects which are seen with these class of drugs. In patients with H.pylori infection which is implicated in the development of gastric carcinoma, it was observed that HSPs contributed to the progression of H. pylori-associated gastric carcinogenesis as well as led to the aggravation of gastric inflammation.33 Table 1: Functions of Heat Shock Proteins Family Function HSP90 (constitutive, induced)4 - 8 -          Regulatory interactions with signalling proteins -          Protein synthesis, folding and degradation -          Stabilization of misfolded proteins -          Binding of estrogen, progesterone, androgen, and aldosterone 5 -          Delivery of antigens to APCs 6 -          Cancer cells: enhances growth, supresses senescence, provides resistance to stress induced apoptosis. 7   -          Cardioprotective: binds to NO synthase and Guanylate cyclase, cause vascular relaxation  8 HSP70 (constitutive) 6, 9 - 12 -          Protein folding, membrane transport of proteins 9 -          Anti-apoptotic 10 -          Delivery of antigens to APCs 6 -          In sympathetic neurons: 11 •      HSP 72 – inhibits degradation of Tau protein, heat shock inducible •      HSC 70 - promotes degradation of Tau protein Low levels – associated with insulin resistance 12 HSP60 (constitutive) -          In the mitochondria, replication and transcription of DNA, pro-survival. 13 -          In the cytosol, complexes and inhibits maturation and activation of Caspase 3 – Anti apoptotic 14 -          At the surface and extracellularly, stimulates immune response 15 HSP40 -          Protein folding, co-chaperon for HSP70 16 -          HSP40-70 complex – modulate accumulation of polyglutamine proteins 17 HSP27 (β1) (induced) -          Anti-apoptotic, prevents proteolysis by inhibiting liberation of cytochrome c from mitochondria18 Small HSPs -          Stabilization of misfolded proteins19 Table 2: Drugs acting via HSPs Family Drug Disease Against HSP90 Geldanamycin (derivative, 17-allylamine,17-demethoxigeldanamycin) Malaria20 Huntington’s disease21 Cacncers22,23 Efungumab Invasive Candidiasis24 Against HSP70 Triptolide Pancreatic cancer25 Mesothelioma26 Methylene blue (inhibits ATPase activity of HSP72) Alzheimer’s disease27 Pro-HSP60 Bortezomib28 Malignancies, increases expression of HSP60 on malignant cells and thus enhances immune response against tumour cells Against HSP40 Quercetin (inhibits HSP 40 and 27) Parkinson’s disease29 Cancer30 Against HSP27 Apatorsen (antisense oligonucleotide) Cancer31 Diagnostic tool32 Increased levels - Renal injury and fibrosis, Cancers of breast, lung, liver, prostate, rectal, osteosarcoma, leukaemia, cerebral and cardiac ischemia Reduced levels – oesophageal cancer Anti-HSP27 IgA – Gynaecological malignancies Against HSP70 Triptolide Pancreatic cancer25 Mesothelioma26 Methylene blue (inhibits ATPase activity of HSP72) Alzheimer’s disease27 Pro-HSP60 Bortezomib28 Malignancies, increases expression of HSP60 on malignant cells and thus enhances immune response against tumour cells Against HSP40 Quercetin (inhibits HSP 40 and 27) Parkinson’s disease29 Cancer30 Against HSP27 Apatorsen (antisense oligonucleotide) Cancer31 Diagnostic tool32 Increased levels - Renal injury and fibrosis, Cancers of breast, lung, liver, prostate, rectal, osteosarcoma, leukaemia, cerebral and cardiac ischemia Reduced levels – oesophageal cancer Anti-HSP27 IgA – Gynaecological malignancies   Autoimmune disease: Since these are highly conserved in nature, they are the initiators as well as the targets of autoimmune attack. Molecular mimicry and cross presentation of antigens are the phenomena of their involvement in autoimmunity. Their roles have been implicated in atherosclerosis, uveitis, lupus and Behcet’s disease. 34 Atherosclerosis: Risk factors for atherosclerosis including infection, oxidative stress, biomechanical stress, all lead to the overproduction of HSPs through the activation of heat shock transcription factor 1 which may lead to worsening of atherosclerosis.35 The anti-apoptotic property may lead to a poor prognosis and resistance to therapy in cancer which the anti-apoptotic activity may be therapeutically advantageous.36 Insomnia or sleep deprivation can lead to an increased level of HSPs acting as a neuroprotective response, emphasizing on the role of adequate sleep in disease prevention.37 CONCLUSION Harms and benefits are two sides of the same coin, as is the case with heat shock proteins. Despite their presence ubiquitously, a small rise or fall in their levels can have a different specific new set of adverse implications. However, despite the availability of information, further research in needed in order to develop newer drugs which may prove beneficial in the treatment of difficult, incurable diseases. REFERENCES Schlesinger, M. J. (1990). Heat shock proteins. The Journal of Biological Chemistry, 265(21), 12111–12114. PMid:2197269 Lindquist, S., & Craig, E. A. (1988). The heat-shock proteins. Annual review of genetics, 22(1), 631-677. https://doi.org/10.1146/annurev.ge.22.120188.003215, PMid:2853609 Wirth, D., Gustin, P., Drion, P., Dessy-Doize, C., & Christians, E. S. (2002). Heat shock proteins. I: Classification and roles in pathological processes. In Annales de Médecine Vétérinaire (Vol. 146, No. 4, pp. 201-216). Annales Medecine Veterinaire. Jackson, S. E. (2012). Hsp90: structure and function. In Molecular chaperones(pp. 155-240). Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2012_356, PMid:22955504 Joab, I., Radanyi, C., Renoir, M., Buchou, T., Catelli, M. G., Binart, N., ... & Baulieu, E. E. (1984). Common non-hormone binding component in non-transformed chick oviduct receptors of four steroid hormones. Nature, 308(5962), 850. https://doi.org/10.1038/308850a0, PMid:6201744 Gaston, J. S. H. (2002). Heat Shock Proteins and Innate immunity. Clin Exp Immunol, 127(1), 1–3. https://doi.org/10.1046/j.1365-2249.2002.01759.x, https://doi.org/10.1111/j.1365-2249.1990.tb05394.x, PMid:11882025, PMCid:PMC1906278 Workman, P., Burrows, F., Neckers, L., & Rosen, N. (2007). Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci, 1113, 202–216. https://doi.org/10.1196/annals.1391.012, PMid:17513464 Antonova, G., Lichtenbeld, H., Xia, T., Chatterjee, A., Dimitropoulou, C., & Catravas J. D. (2007). Functional significance of hsp90 complexes with NOS and sGC in endothelial cells. Clin Hemorheol Microcirc, 37(1-2), 19-35. Hartl, F.U. (1996). Molecular chaperones in cellular protein folding. Nature, 381, 571-579. https://doi.org/10.1038/381571a0, PMid:8637592 Gehrmann, M., Radons, J., Molls, M., & Multhoff, G. (2008). The therapeutic implications of clinically applied modifiers of heat shock protein 70 (Hsp70) expression by tumor cells. Cell Stress Chaperones, 13(1), 1-10. https://doi.org/10.1007/s12192-007-0006-0, PMid:18347936, PMCid:PMC2666213 Jinwal, U. K., Akoury, E., Abisambra, J. F., O'Leary, J. C., Thompson, A.D., Blair, L. J., et al. (2013). Imbalance of Hsp70 family variants fosters tau accumulation. FASEB J, 27(4), 1450-1459. https://doi.org/10.1096/fj.12-220889, PMid:23271055, PMCid:PMC3606536 Chichester, L., Wylie, A. T., Craft, S., & Kavanagh, K. (2015). Muscle heat shock protein 70 predicts insulin resistance with aging. J Gerontol A Biol Sci Med Sci, 70(2), 155-62. https://doi.org/10.1093/gerona/glu015, PMid:24532784, PMCid:PMC4311181 Kaufman, B. A., Kolesar, J. E., Perlman, P. S., & Butow, R. A. (2003). A function for the mitochondrial chaperonin Hsp60 in the structure and transmission of mitochondrial DNA nucleoids in Saccharomyces cerevisiae. J Cell Biol, 163, 457-461. https://doi.org/10.1083/jcb.200306132, PMid:14597775, PMCid:PMC2173642 Xanthoudakis, S., Roy, S., Rasper, D., Hennessey, T., Aubin, Y., Cassady, R., et al. (1999). Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis. EMBO J, 18(18), 2049-2056. https://doi.org/10.1093/emboj/18.8.2049, PMid:10205159, PMCid:PMC1171289 Pockley, A. G., Muthana, M., & Calderwood, S. K. (2008). The dual immunoregulatory roles of stress proteins. Trends Biochem Sci, 33, 71-79. https://doi.org/10.1016/j.tibs.2007.10.005, PMid:18182297 Castanie-Cornet, M. P., Bruel, N., & Genevaux, P. (2014). Chaperone networking facilitates protein targeting to the bacterial cytoplasmic membrane. Biochim Biophys. Acta, 1843, 1442-1456. https://doi.org/10.1016/j.bbamcr.2013.11.007, PMid:24269840 Wacker, J. L., Zareie, M. H., Fong, H., Sarikaya, M., & Muchowski, P. J. (2004). Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nature Structural & Molecular Biology, 11(12), 1215-1222. https://doi.org/10.1038/nsmb860, PMid:15543156 Paul, C., Manero, F., Gonin, S., Kretz-Remy, C., Virot, S., & Arrigo, A. P. (2002). Hsp27 as a negative regulator of cytochrome C release. Mol Cell Biol, 22(3):816-34. https://doi.org/10.1128/MCB.22.3.816-834.2002, PMid:11784858, PMCid:PMC133538 Ungelenk, S., Moayed, F., Ho, C. T., Grousl, T., Scharf, A., Mashaghi, A., et al. (2016). Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding. Nature Communications, 7, Article number: 13673. https://doi.org/10.1038/ncomms13673, PMid:27901028, PMCid:PMC5141385 Wang, T., Maser, P., & Picard, D. (2016). Inhibition of Plasmodium falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-carbazoles. Med. Chem., 59(13), 6344–6352. https://doi.org/10.1021/acs.jmedchem.6b00591, PMid:27312008 Sittler, A., Lurz, R., Lueder, G., Priller, J., Lehrach, H., Hayer-Hartl, M. K., et al. (2001). Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease. Human Molecular Genetics, 10(12), 1307-1315. https://doi.org/10.1093/hmg/10.12.1307, PMid:11406612 Jurczyszyn, A., Zebzda, A., Czepiel, J., Perucki, W., Bazan-Socha, S., Cibor, D., et al. (2014). Geldanamycin and Its Derivatives Inhibit the Growth of Myeloma Cells and Reduce the Expression of the MET Receptor. J Cancer, 5(6), 480–490. https://doi.org/10.7150/jca.8731, PMid:24959301, PMCid:PMC4066360 Li, Y., Zhang, T., & Sun, D. (2009). New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential. Drug Resist Updat, 12(1-2), 17–27. https://doi.org/10.1016/j.drup.2008.12.002, PMid:19179103, PMCid:PMC2692088 Karwa, R., & Wargo, K. A. (2009). Efungumab: a novel agent in the treatment of invasive candidiasis. Ann Pharmacother, 43(11), 1818-1823. https://doi.org/10.1345/aph.1M218, PMid:19773528 Phillips, P. A., Dudeja, V., McCarroll, J.A., Borja-Cacho, D., Dawra, R. K., Grizzle, W. E., et al. (2007). Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res, 67(19), 9407-9416. https://doi.org/10.1158/0008-5472.CAN-07-1077, PMid:17909050 Jacobson, B. A., Chen, E. Z., Tang, S., Belgum, H. S., McCauley, J. A., Evenson, K. A., et al. (2015). Triptolide and its prodrug minnelide suppress Hsp70 and inhibit in vivo growth in a xenograft model of mesothelioma. Genes Cancer, 6(3-4), 144–152. PMid:26000097, PMCid:PMC4426951 O'Leary, J. C., Li, Q., Marinec, P., Blair, L. J., Congdon, E. E., Johnson, A. G., et al. (2010). Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Molecular Neurodegeneration, 5(1), Article 45. https://doi.org/10.1186/1750-1326-5-45, PMid:21040568, PMCid:PMC2989315 Chang, C. L., Hsu, Y. T., Wu. C. C., Yang, Y. C., Wang, C., Wu, T. C., et al. (2012). Immune mechanism of the antitumor effects generated by bortezomib. J Immunol, 189(6), 3209-3220. https://doi.org/10.4049/jimmunol.1103826, PMid:22896634 Ekimov, I. V., & Plaksina, D. V. (2017). Effects of Quercetin on Neurodegenerative and Compensatory Processes in the Nigrostriatal System in a Model of the Preclinical Stage of Parkinson’s Disease in Rats. Neuroscience and Behavioral Physiology, 47(9), 1029–1036. https://doi.org/10.1007/s11055-017-0508-x McConnell, J. R., & McAlpine, S. R. (2013). Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets. Bioorg Med Chem Lett, 23(7), 1923–1928. https://doi.org/10.1016/j.bmcl.2013.02.014, PMid:23453837, PMCid:PMC3602338 Chi, K. N., Yu, E. Y., Jacobs, C., Bazov, J., Kollmannsberger, C., Higano, C.S., et al. (2016). A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers. Ann Oncol, 27(6), 1116-1122. https://doi.org/10.1093/annonc/mdw068, PMid:27022067 Vidyasagar, A., Wilson, N. A., & Djamali, A. (2012). Heat shock protein 27 (HSP27): biomarker of disease and therapeutic target. Fibrogenesis & Tissue Repair, 5(1), 7. https://doi.org/10.1186/1755-1536-5-7, PMid:22564335, PMCid:PMC3464729 Lee, H. J., Ock, C.Y., Kin, S. J., & Hahm, K. B. (2010). Heat Shock Protein: Hard Worker or Bad Offender for Gastric Diseases. International Journal of Proteomics, 2010, 1-11. https://doi.org/10.1155/2010/259163, PMid:22084675, PMCid:PMC3195352 Moudgil, K. D., Thompson, S. J., Geraci, F., Paepe, B. D., & Shoenfeld, Y. (2013). Heat-Shock Proteins in Autoimmunity. Autoimmune Diseases, 2013; 1-3. https://doi.org/10.1155/2013/621417 Xu, Q. (2002). Role of Heat Shock Proteins in Atherosclerosis. Atherosclerosis, Thrombosis and Vascular biology, 22, 1547-1559. https://doi.org/10.1161/01.ATV.0000029720.59649.50 Calderwood, S.K., & Gong, J. (2016). Heat Shock Proteins Promote Cancer: It's a Protection Racket. Trends in Biochemical Sciences, 41(4), 311-323. https://doi.org/10.1016/j.tibs.2016.01.003, PMid:26874923, PMCid:PMC4911230 Terao, A., Steininger, T. L., Hyder, K., Apte-Deshpande, A., Ding, J., Rishipathak, D., et al. (2003). Differential increase in the expression of heat shock protein family members during sleep deprivation and during sleep. Neuroscience, 116(1), 187-200. https://doi.org/10.1016/S0306-4522(02)00695-4 Read the full article

[journalsclub-blog]

Heat Shock Proteins, a short review

INTRODUCTION Stressful conditions trigger certain defence mechanisms, including those at molecular levels. This was first seen in Drosophilia and was reported in 1974.1 Heat Shock Proteins (HSPs), also known as Stress-induced Proteins or Stress Proteins, are one such class of proteins that are produced in the body in response to stress, under the control of Heat Shock Factors (HSFs), although some are constitutively expressed. The stress may be heat, cold, UV radiation, infections, inflammation, heavy metal exposure or else. HSPs are produced by all organisms and are ubiquitously present. The primary involvement of these proteins is in the folding and stabilization of other proteins, and thus they play an intimate role in the aggregation of various other proteins.2 Besides action on protein folding, these HSPs also possess pro- and anti-apoptotic properties, making them suitable targets for drug development. The HSP families are classified according to their molecular weight.3 Table 1 describes in brief the classification as well as a few functions of these proteins. In the recent past, various drug have been developed which act in line or against the HSPs but a still in their infancy. Besides drugs, the HSPs are also employed as diagnostic tools in various cancers. These are referenced in Table 2. The flip side is the new set of adverse effects which are seen with these class of drugs. In patients with H.pylori infection which is implicated in the development of gastric carcinoma, it was observed that HSPs contributed to the progression of H. pylori-associated gastric carcinogenesis as well as led to the aggravation of gastric inflammation.33 Table 1: Functions of Heat Shock Proteins Family Function HSP90 (constitutive, induced)4 - 8 -          Regulatory interactions with signalling proteins -          Protein synthesis, folding and degradation -          Stabilization of misfolded proteins -          Binding of estrogen, progesterone, androgen, and aldosterone 5 -          Delivery of antigens to APCs 6 -          Cancer cells: enhances growth, supresses senescence, provides resistance to stress induced apoptosis. 7   -          Cardioprotective: binds to NO synthase and Guanylate cyclase, cause vascular relaxation  8 HSP70 (constitutive) 6, 9 - 12 -          Protein folding, membrane transport of proteins 9 -          Anti-apoptotic 10 -          Delivery of antigens to APCs 6 -          In sympathetic neurons: 11 •      HSP 72 – inhibits degradation of Tau protein, heat shock inducible •      HSC 70 - promotes degradation of Tau protein Low levels – associated with insulin resistance 12 HSP60 (constitutive) -          In the mitochondria, replication and transcription of DNA, pro-survival. 13 -          In the cytosol, complexes and inhibits maturation and activation of Caspase 3 – Anti apoptotic 14 -          At the surface and extracellularly, stimulates immune response 15 HSP40 -          Protein folding, co-chaperon for HSP70 16 -          HSP40-70 complex – modulate accumulation of polyglutamine proteins 17 HSP27 (β1) (induced) -          Anti-apoptotic, prevents proteolysis by inhibiting liberation of cytochrome c from mitochondria18 Small HSPs -          Stabilization of misfolded proteins19 Table 2: Drugs acting via HSPs Family Drug Disease Against HSP90 Geldanamycin (derivative, 17-allylamine,17-demethoxigeldanamycin) Malaria20 Huntington’s disease21 Cacncers22,23 Efungumab Invasive Candidiasis24 Against HSP70 Triptolide Pancreatic cancer25 Mesothelioma26 Methylene blue (inhibits ATPase activity of HSP72) Alzheimer’s disease27 Pro-HSP60 Bortezomib28 Malignancies, increases expression of HSP60 on malignant cells and thus enhances immune response against tumour cells Against HSP40 Quercetin (inhibits HSP 40 and 27) Parkinson’s disease29 Cancer30 Against HSP27 Apatorsen (antisense oligonucleotide) Cancer31 Diagnostic tool32 Increased levels - Renal injury and fibrosis, Cancers of breast, lung, liver, prostate, rectal, osteosarcoma, leukaemia, cerebral and cardiac ischemia Reduced levels – oesophageal cancer Anti-HSP27 IgA – Gynaecological malignancies Against HSP70 Triptolide Pancreatic cancer25 Mesothelioma26 Methylene blue (inhibits ATPase activity of HSP72) Alzheimer’s disease27 Pro-HSP60 Bortezomib28 Malignancies, increases expression of HSP60 on malignant cells and thus enhances immune response against tumour cells Against HSP40 Quercetin (inhibits HSP 40 and 27) Parkinson’s disease29 Cancer30 Against HSP27 Apatorsen (antisense oligonucleotide) Cancer31 Diagnostic tool32 Increased levels - Renal injury and fibrosis, Cancers of breast, lung, liver, prostate, rectal, osteosarcoma, leukaemia, cerebral and cardiac ischemia Reduced levels – oesophageal cancer Anti-HSP27 IgA – Gynaecological malignancies   Autoimmune disease: Since these are highly conserved in nature, they are the initiators as well as the targets of autoimmune attack. Molecular mimicry and cross presentation of antigens are the phenomena of their involvement in autoimmunity. Their roles have been implicated in atherosclerosis, uveitis, lupus and Behcet’s disease. 34 Atherosclerosis: Risk factors for atherosclerosis including infection, oxidative stress, biomechanical stress, all lead to the overproduction of HSPs through the activation of heat shock transcription factor 1 which may lead to worsening of atherosclerosis.35 The anti-apoptotic property may lead to a poor prognosis and resistance to therapy in cancer which the anti-apoptotic activity may be therapeutically advantageous.36 Insomnia or sleep deprivation can lead to an increased level of HSPs acting as a neuroprotective response, emphasizing on the role of adequate sleep in disease prevention.37 CONCLUSION Harms and benefits are two sides of the same coin, as is the case with heat shock proteins. Despite their presence ubiquitously, a small rise or fall in their levels can have a different specific new set of adverse implications. However, despite the availability of information, further research in needed in order to develop newer drugs which may prove beneficial in the treatment of difficult, incurable diseases. REFERENCES Schlesinger, M. J. (1990). Heat shock proteins. The Journal of Biological Chemistry, 265(21), 12111–12114. PMid:2197269 Lindquist, S., & Craig, E. A. (1988). The heat-shock proteins. Annual review of genetics, 22(1), 631-677. https://doi.org/10.1146/annurev.ge.22.120188.003215, PMid:2853609 Wirth, D., Gustin, P., Drion, P., Dessy-Doize, C., & Christians, E. S. (2002). Heat shock proteins. I: Classification and roles in pathological processes. In Annales de Médecine Vétérinaire (Vol. 146, No. 4, pp. 201-216). Annales Medecine Veterinaire. Jackson, S. E. (2012). Hsp90: structure and function. In Molecular chaperones(pp. 155-240). Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2012_356, PMid:22955504 Joab, I., Radanyi, C., Renoir, M., Buchou, T., Catelli, M. G., Binart, N., ... & Baulieu, E. E. (1984). Common non-hormone binding component in non-transformed chick oviduct receptors of four steroid hormones. Nature, 308(5962), 850. https://doi.org/10.1038/308850a0, PMid:6201744 Gaston, J. S. H. (2002). Heat Shock Proteins and Innate immunity. Clin Exp Immunol, 127(1), 1–3. https://doi.org/10.1046/j.1365-2249.2002.01759.x, https://doi.org/10.1111/j.1365-2249.1990.tb05394.x, PMid:11882025, PMCid:PMC1906278 Workman, P., Burrows, F., Neckers, L., & Rosen, N. (2007). Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci, 1113, 202–216. https://doi.org/10.1196/annals.1391.012, PMid:17513464 Antonova, G., Lichtenbeld, H., Xia, T., Chatterjee, A., Dimitropoulou, C., & Catravas J. D. (2007). Functional significance of hsp90 complexes with NOS and sGC in endothelial cells. Clin Hemorheol Microcirc, 37(1-2), 19-35. Hartl, F.U. (1996). Molecular chaperones in cellular protein folding. Nature, 381, 571-579. https://doi.org/10.1038/381571a0, PMid:8637592 Gehrmann, M., Radons, J., Molls, M., & Multhoff, G. (2008). The therapeutic implications of clinically applied modifiers of heat shock protein 70 (Hsp70) expression by tumor cells. Cell Stress Chaperones, 13(1), 1-10. https://doi.org/10.1007/s12192-007-0006-0, PMid:18347936, PMCid:PMC2666213 Jinwal, U. K., Akoury, E., Abisambra, J. F., O'Leary, J. C., Thompson, A.D., Blair, L. J., et al. (2013). Imbalance of Hsp70 family variants fosters tau accumulation. FASEB J, 27(4), 1450-1459. https://doi.org/10.1096/fj.12-220889, PMid:23271055, PMCid:PMC3606536 Chichester, L., Wylie, A. T., Craft, S., & Kavanagh, K. (2015). Muscle heat shock protein 70 predicts insulin resistance with aging. J Gerontol A Biol Sci Med Sci, 70(2), 155-62. https://doi.org/10.1093/gerona/glu015, PMid:24532784, PMCid:PMC4311181 Kaufman, B. A., Kolesar, J. E., Perlman, P. S., & Butow, R. A. (2003). A function for the mitochondrial chaperonin Hsp60 in the structure and transmission of mitochondrial DNA nucleoids in Saccharomyces cerevisiae. J Cell Biol, 163, 457-461. https://doi.org/10.1083/jcb.200306132, PMid:14597775, PMCid:PMC2173642 Xanthoudakis, S., Roy, S., Rasper, D., Hennessey, T., Aubin, Y., Cassady, R., et al. (1999). Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis. EMBO J, 18(18), 2049-2056. https://doi.org/10.1093/emboj/18.8.2049, PMid:10205159, PMCid:PMC1171289 Pockley, A. G., Muthana, M., & Calderwood, S. K. (2008). The dual immunoregulatory roles of stress proteins. Trends Biochem Sci, 33, 71-79. https://doi.org/10.1016/j.tibs.2007.10.005, PMid:18182297 Castanie-Cornet, M. P., Bruel, N., & Genevaux, P. (2014). Chaperone networking facilitates protein targeting to the bacterial cytoplasmic membrane. Biochim Biophys. Acta, 1843, 1442-1456. https://doi.org/10.1016/j.bbamcr.2013.11.007, PMid:24269840 Wacker, J. L., Zareie, M. H., Fong, H., Sarikaya, M., & Muchowski, P. J. (2004). Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nature Structural & Molecular Biology, 11(12), 1215-1222. https://doi.org/10.1038/nsmb860, PMid:15543156 Paul, C., Manero, F., Gonin, S., Kretz-Remy, C., Virot, S., & Arrigo, A. P. (2002). Hsp27 as a negative regulator of cytochrome C release. Mol Cell Biol, 22(3):816-34. https://doi.org/10.1128/MCB.22.3.816-834.2002, PMid:11784858, PMCid:PMC133538 Ungelenk, S., Moayed, F., Ho, C. T., Grousl, T., Scharf, A., Mashaghi, A., et al. (2016). Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding. Nature Communications, 7, Article number: 13673. https://doi.org/10.1038/ncomms13673, PMid:27901028, PMCid:PMC5141385 Wang, T., Maser, P., & Picard, D. (2016). Inhibition of Plasmodium falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-carbazoles. Med. Chem., 59(13), 6344–6352. https://doi.org/10.1021/acs.jmedchem.6b00591, PMid:27312008 Sittler, A., Lurz, R., Lueder, G., Priller, J., Lehrach, H., Hayer-Hartl, M. K., et al. (2001). Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease. Human Molecular Genetics, 10(12), 1307-1315. https://doi.org/10.1093/hmg/10.12.1307, PMid:11406612 Jurczyszyn, A., Zebzda, A., Czepiel, J., Perucki, W., Bazan-Socha, S., Cibor, D., et al. (2014). Geldanamycin and Its Derivatives Inhibit the Growth of Myeloma Cells and Reduce the Expression of the MET Receptor. J Cancer, 5(6), 480–490. https://doi.org/10.7150/jca.8731, PMid:24959301, PMCid:PMC4066360 Li, Y., Zhang, T., & Sun, D. (2009). New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential. Drug Resist Updat, 12(1-2), 17–27. https://doi.org/10.1016/j.drup.2008.12.002, PMid:19179103, PMCid:PMC2692088 Karwa, R., & Wargo, K. A. (2009). Efungumab: a novel agent in the treatment of invasive candidiasis. Ann Pharmacother, 43(11), 1818-1823. https://doi.org/10.1345/aph.1M218, PMid:19773528 Phillips, P. A., Dudeja, V., McCarroll, J.A., Borja-Cacho, D., Dawra, R. K., Grizzle, W. E., et al. (2007). Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res, 67(19), 9407-9416. https://doi.org/10.1158/0008-5472.CAN-07-1077, PMid:17909050 Jacobson, B. A., Chen, E. Z., Tang, S., Belgum, H. S., McCauley, J. A., Evenson, K. A., et al. (2015). Triptolide and its prodrug minnelide suppress Hsp70 and inhibit in vivo growth in a xenograft model of mesothelioma. Genes Cancer, 6(3-4), 144–152. PMid:26000097, PMCid:PMC4426951 O'Leary, J. C., Li, Q., Marinec, P., Blair, L. J., Congdon, E. E., Johnson, A. G., et al. (2010). Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Molecular Neurodegeneration, 5(1), Article 45. https://doi.org/10.1186/1750-1326-5-45, PMid:21040568, PMCid:PMC2989315 Chang, C. L., Hsu, Y. T., Wu. C. C., Yang, Y. C., Wang, C., Wu, T. C., et al. (2012). Immune mechanism of the antitumor effects generated by bortezomib. J Immunol, 189(6), 3209-3220. https://doi.org/10.4049/jimmunol.1103826, PMid:22896634 Ekimov, I. V., & Plaksina, D. V. (2017). Effects of Quercetin on Neurodegenerative and Compensatory Processes in the Nigrostriatal System in a Model of the Preclinical Stage of Parkinson’s Disease in Rats. Neuroscience and Behavioral Physiology, 47(9), 1029–1036. https://doi.org/10.1007/s11055-017-0508-x McConnell, J. R., & McAlpine, S. R. (2013). Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets. Bioorg Med Chem Lett, 23(7), 1923–1928. https://doi.org/10.1016/j.bmcl.2013.02.014, PMid:23453837, PMCid:PMC3602338 Chi, K. N., Yu, E. Y., Jacobs, C., Bazov, J., Kollmannsberger, C., Higano, C.S., et al. (2016). A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers. Ann Oncol, 27(6), 1116-1122. https://doi.org/10.1093/annonc/mdw068, PMid:27022067 Vidyasagar, A., Wilson, N. A., & Djamali, A. (2012). Heat shock protein 27 (HSP27): biomarker of disease and therapeutic target. Fibrogenesis & Tissue Repair, 5(1), 7. https://doi.org/10.1186/1755-1536-5-7, PMid:22564335, PMCid:PMC3464729 Lee, H. J., Ock, C.Y., Kin, S. J., & Hahm, K. B. (2010). Heat Shock Protein: Hard Worker or Bad Offender for Gastric Diseases. International Journal of Proteomics, 2010, 1-11. https://doi.org/10.1155/2010/259163, PMid:22084675, PMCid:PMC3195352 Moudgil, K. D., Thompson, S. J., Geraci, F., Paepe, B. D., & Shoenfeld, Y. (2013). Heat-Shock Proteins in Autoimmunity. Autoimmune Diseases, 2013; 1-3. https://doi.org/10.1155/2013/621417 Xu, Q. (2002). Role of Heat Shock Proteins in Atherosclerosis. Atherosclerosis, Thrombosis and Vascular biology, 22, 1547-1559. https://doi.org/10.1161/01.ATV.0000029720.59649.50 Calderwood, S.K., & Gong, J. (2016). Heat Shock Proteins Promote Cancer: It's a Protection Racket. Trends in Biochemical Sciences, 41(4), 311-323. https://doi.org/10.1016/j.tibs.2016.01.003, PMid:26874923, PMCid:PMC4911230 Terao, A., Steininger, T. L., Hyder, K., Apte-Deshpande, A., Ding, J., Rishipathak, D., et al. (2003). Differential increase in the expression of heat shock protein family members during sleep deprivation and during sleep. Neuroscience, 116(1), 187-200. https://doi.org/10.1016/S0306-4522(02)00695-4 Read the full article

[brainitec]

Digital marketing is a team effort everyone in the team has a different role to play. The techniques and the strategies associated with digital marketing contribute differently and the entire team has to work in a disciplined manner for a common goal. Click to find out Best Digital marketing company in Pune.

 The digital entrepreneurs and industry insiders have put up an enormous impact on digital marketing services. Let's see what the industry insiders like Michael Sharkey, Becca Lindquist, and Tyson Quicksay say about Digital marketing.

 The co-founder and CEO of Autopilot, Michael Sharkey says that the digital market is revolutionized by selling cloud services to the customers which helps the marketers to decide which application to use to make purchase decisions. It has become much secured to store, manage and process the data for digital marketing.

Specifically, the global public cloud service market has seen remarkable growth of about 35% in the year 2018.

According to Becca Lindquist, Head of new businesses ‘Heap”, the online business persons should market their services like the year they are in. She also says that marketers do not find the customers for the products and services but find out the products and services required by the customers. There are many consumers who are expecting a consistent experience in this digital industry.

A founder and CEO of  “Instapage” Tyson Quick says that Digital marketing has made huge signs of progress as many companies can now individually offer the entire marketing technology suite of tools to the customers. The trends in marketing have changed to a large extent.

The director of Content Marketing at Segment Mr. Brent Summers in his recent interview said that today the condition of marketing technology is a mess as it is facing a proliferation of tools in the past few years. He says that the content is the hero of digital marketing. As according to him the consumers absorbs the content before making any purchasing decision. He emphasizes on to produce quality content instead of depending on fragmented tools available.

The head of digital marketing at Prezi Mr. Harley Butler says that the concept of big data helps in understanding the demands of the clients and it also determines the preferences and the behavioral trends of the customers. He also says that now the digital marketing is capable of synthesizing the data into actionable marketing techniques. He added that it has started to pay from an ROI’s perspective. Improve your websites organic ranking by SEO Company in Pune.

The world of digital marketing going through many changes and alterations and finding tools and tricks for digital marketing has become very easy just by keeping ourself up-to-date with the opinions and observations of the leading industry insiders in the field of digital marketing

[q-u-4-blog]

Blandet drops.

[marcusssanderson]

50 Quotes With Life Lessons to Help You Move On

Our latest collection of quotes on life lessons on Everyday Power Blog.

It’s easy to go through life living in regrets and focusing on the negative things of the past. It can be a challenge to shake off what has held you back and move forward towards a bright future.

But as long as you focus on the negative baggage from yesterday, it’s going to keep you from getting to where you want to go. Focusing on your past mistakes, what hurt you and what didn’t work out can only stop you from the bright future you envisioned.

To start afresh and move forward, there are a lot of things you are going to want to drop. Whether it’s a betrayal, bad childhood, divorce, or bad job, you have to let it go and move forward.

You cannot do anything about what happened in the past but you can do something about your future. Your past is not as important as what’s ahead; so you cannot let it poison your future.

There’s a lot the world can teach us. Here are some powerful quotes on life lessons to inspire you to live a happier, healthier and more meaningful life.

  Quotes with life lessons to help you move on

  1.) “‎Though nobody can go back and make a new beginning… Anyone can start over and make a new ending.” ― Chico Xavier

  2.) “Every new beginning comes from some other beginning’s end.” –  Seneca

  3.) “I do a good job of staying positive and just moving on.” – Katie Taylor

  4.) “You can only lose what you cling to.”— Buddha

    5.) “Courage is the most important of all the virtues because without courage, you can’t practice any other virtue consistently.” ― Maya Angelou

  6.) “Every defeat, every heartbreak, every loss, contains its own seed, its own lesson on how to improve your performance the next time.” – Og Mandino

  7.) “You only struggle because you’re ready to grow but aren’t willing to let go.” – Drew Gerald

  8.) “It’s time to say goodbye, but I think goodbyes are sad and I’d much rather say hello. Hello to a new adventure.” – Ernie Harwell

  9.) “Courage is the power to let go of the familiar.”– Raymond Lindquist

  10.) “It happens to everyone as they grow up. You find out who you are and what you want, and then you realize that people you’ve known forever don’t see things the way you do. So you keep the wonderful memories, but find yourself moving on.” ― Nicholas Sparks

  Quotes about life lessons and moving on

  11.) “The past is a place of reference, not a place of residence; the past is a place of learning, not a place of living.” ― Roy T. Bennett

  12.) “Letting go does not mean you stop caring. It means you stop trying to force others to.”– Mandy Hale

  13.) “In three words I can sum up everything I’ve learned about life: it goes on.” – Robert Frost

  14.) “Yesterday is not ours to recover, but tomorrow is ours to win or lose.”– Lyndon B. Johnson

    15.) “Every day is a new day, and you’ll never be able to find happiness if you don’t move on.” –  Carrie Underwood

  16.) “Think of each failure, each heartache, and each loss in your life as a lesson in courage and resilience.” – Kate Anderson

  17.) “Anything you can’t control is teaching you how to let go.” – Jackson Kiddard

  18.) “You can’t move forward if you’re still hanging on.” – Sue Fitzmaurice

  19.) “Nothing in the universe can stop you from letting go and starting over.”– Guy Finley

  20.) “Letting go doesn’t mean that you don’t care about someone anymore. It’s just realizing that the only person you really have control over is yourself.” ― Deborah Reber

  Inspirational quotes on life lessons

  21.) “If there’s a single lesson that life teaches us, it’s that wishing doesn’t make it so.” ― Lev Grossman

  22.) “My greatest life lessons have not come from any achievements I have attained but rather from the failures, heartaches, and setbacks that I have experienced.” – Dr. Marshall Hennington

  23.) “Sooner or later we’ve all got to let go of our past.”– Dan Brown

  24.) “It’s not the mistake that matters, it’s how you interpret the lesson.” – Michelle C. Ustaszeski

  25.) “Letting go isn’t a one-time thing, it’s something you have to do every day, over and over again.” – Dawson’s Creek

  26.) “Why let go of yesterday? Because yesterday has already let go of you.” – Steve Maraboli

    27.) “I am learning to love the sound of my feet walking away from things not meant for me.” – A.G.

  28.) “Your past does not equal your future.”– Anthony Robbins

  29.) “Sometimes the hardest part isn’t letting go but rather learning to start over.” ― Nicole Sobon

  30.) “You don’t have to let that one thing be the thing that defines you.” ― Jojo Moyes

  Quotes about life lessons and mistakes

  31.) “We are products of our past, but we don’t have to be prisoners of it.” ― Rick Warren

  32.) “Forgive yourself for your faults and your mistakes and move on.” – Les Brown

  33.) “Some of us think holding on makes us strong, but sometimes it is letting go.”– Herman Hesse

  34.) “Most people claim that they feel like they’re trapped in a rat race, without an exit. While we can all feel this way from time to time, it’s important to know that there is a way out.” – Debeena Harris

  35.) “Only the dead have seen the end of war.” ― Plato

    36.) “You don’t learn to walk by following rules. You learn by doing, and by falling over.” ― Richard Branson

  37.) “A man must be big enough to admit his mistakes, smart enough to profit from them, and strong enough to correct them.” – John C. Maxwell

  38.) “We all make them, the difference is what we do after we make the mistake, how we see the mistake – a learning experience or a failure.” – Catherine Pulsifer

  39.) “You make mistakes. Mistakes don’t make you.” – Maxwell Maltz

  40.) “There is no sense in punishing your future for the mistakes of your past. Forgive yourself, grow from it, and then let it go.” – Melanie Koulouris

  Other motivational quotes on life lessons

  41.) “The great courageous act that we must all do, is to have the courage to step out of our history and past so that we can live our dreams.” ― Oprah Winfrey

  42.) “We must be willing to let go of the life we’ve planned, so as to have the life that is waiting for us.”– Joseph Campbell

  43.) “Over the years I’ve come to realize that mistakes are just lessons, life lessons almost like school. Once you’ve learned a lesson in class, you move on to the next lesson because now you know it. Well mistakes are exactly the same.” – Rashard Royster

  44.) “One of the most courageous decisions you’ll ever make is to finally let go of what is hurting your heart and soul.” – B. Nicole

  45.) “Happiness is not the absence of problems, it’s the ability to deal with them.” ― Steve Maraboli

  46.) “You’ve gotta know when it’s time to turn the page.” – Tori Amos

    47.) “When one door closes, another opens; but we often look so long and so regretfully upon the closed door that we do not see the one which has opened for us.”– Alexander Graham Bell

  48.) “There comes a time in your life when you have to choose to turn the page, write another book or simply close it.” ― Shannon L. Alder

  49.) “A very wise man once told me that you can’t look back-you just have to put the past behind you, and find something better in your future.” ― Jodi Picoult

  50.) “I’ve been burdened with blame trapped in the past for too long, I’m moving on” ― Rascal Flatts

  Which of these quotes on life lessons was your favorite?

Although life can throw a sucker punch at you, you have to stay on course and remain focused on where you want to go. Success is waiting for you; so you cannot live a life limited by fear, anger, ill health, or self-imposed barriers.

Love is all around you. You just have to take the time to feel it for life itself. Hopefully, these quotes have inspired to move on and live life without limits.

Did you enjoy these quotes on life lessons? Which of the quotes was your favorite? Tell us in the comment section below. We would love to hear all about it.

The post 50 Quotes With Life Lessons to Help You Move On appeared first on Everyday Power Blog.

[nbodieshq]

AUDICIONES EN EL BUZÓN. 

Rooney Taggart. (Alycia Debnam-Carey)

Emerald Wicker. (Philippine Stindel)

Roy Sanders (Cameron Monaghan)

EXTENSIÓN DE PLAZOS. 

Toulany (Timothée Chalamet)

OC (Henrik Holm)

OC (Jodie Comer) -cambio de fc de Bella Thorne- 

Murphy (Nick Robinson)

Almeida (Noah Centineo)

Velez (Freya Mavor)

OC (Elizabeth Olsen)

Barnett (Luke Hemmings)

Lindquist (Bill Skarsgaard)

SKELETONS LIBERADOS.

Benally (Madelaine Petsch)

CUENTAS QUE ESPERAMOS.

Daquan Capello.

Winifred Pham.

Joanna Hunnigan.

Nara Jung.

Jezebel Mabbit.

CONTEO GENERAL:

femeninos: 4 cuentas + 2 audiciones + 3 reservas + 4 cuentas en espera: 13 personajes.

masculinos: 2 cuentas + 1 audición + 6 audiciones + 1 cuenta en espera: 10 personajes.

total: 23 personajes. 

NOTAS.

Somos humanos y como todos cometemos errores, por lo cual si ves uno en este listado favor de notificarnos.

Seguimos con las reservas femeninas momentáneamente cerradas, en cuanto tengamos más audiciones se abrirán los cupos

¡Tenemos skeletons todavía libres! Les invitamos a echarles un vistazo y a adoptar a su favorito. 

La opción por segundos personajes queda ahora disponible por un tiempo limitado (suena a oferta de televisión) así que si gustan pueden pasearse por los skeletons o recordar que contamos con 2 OC masculinos todavía abiertos.

Les queremos agradecer de nueva cuenta el apoyo y el tiempo que le han invertido al proyecto, de corazón ya queremos verles por aquí. 

[berthastover]

How to Succeed at Email Marketing in Seasonal Businesses

Seasonal businesses are a tough beast to manage. If you’re running a seasonal business, you’re used to the ups and downs, and the challenges related to managing cash-flow, hiring seasonal labor, and prepping for the swing of things.

As if those things weren’t enough, seasonality throws a wrench into the works when it comes to email marketing, for some reasons, including:

all metrics vary based on your season,

customers subscribe to your list for different reasons at different times of the year,

a great email during the upswing may make no sense during the downturn,

your competitors are also trying to make the most of the busy season.

Here are a few tips on using seasonality to your advantage in your email marketing.

 1. Get an in-depth understanding of your seasonality.

If you are in a seasonal business, you need to have an in-depth understanding of the seasonality, both quantitatively and qualitatively.

You can start by looking at Google trends. What are the main terms people use to describe your product?

Typically, there is a clear trend. I’m in the landscaping industry, which people also describe as ‘lawn care’ and ‘lawn service.’ Looking at the past five years, there’s a pretty clear trend.

  If you’ve been in business for awhile, your revenue graphs will probably align. But your job has just begun. You need to learn much more about your seasonality to beat out your competitors.

Start by talking to your past customers and try and understand their buying process. Ask them questions such as:

● Why did you buy [X]? ● What caused you to buy [X]? ● When did you first hear about [X]? Why did you buy when you did?

Here your goal is to get into the mind of your consumers, searching for tidbits of insight that you might be able to use.

Here’s a lucrative tidbit I learned at LawnStarter. We talked to customers and found that many of them had hired (or tried to hire) a contractor to perform spring cleanups a month or two before mowing the lawn. The natural response? Over winter, we send emails to past customers who may not be looking for lawn mowing, but could probably use yard cleanups. These emails not only get an insanely high conversion rate, but our customers thank us for them.

 2. Understand differences in key metrics.

If you’re in a seasonal business, you can bet key metrics will vary with the seasonality.

Take travel for example. Henry Shi, co-founder and CTO of SnapTravel, says “Christmas week has really poor conversion because ppl are at home with their families, and while they may browse they won’t book. And right after Jan 1, conversion shoots up as people think about their summer travels.”

  Mark Lindquist, a marketing strategist at Milkshake, has seen a similar trend in the B2B SaaS space. “December is always our worst month, and January is always our best. Same goes for a lot of the B2B SaaS businesses I’ve worked with. People just aren’t ready to purchase in December for the following year, but as they start the new year with a fresh budget and big plans for new business initiatives, they start pulling the trigger.”

No two verticals are alike, so be sure to calculate your metrics for your businesses.

In email marketing, there only five metrics that matter:

● Open Rate ● Click Through Rate ● Conversion Rate ● Revenue / Conversion ● Unsubscribe Rate

If you don’t have the data, you can make educated guesses around how these will vary, assuming you understand your seasonality. For example, it’s logical that open rate would drop for an ecommerce site on Black Friday.

However, it’s important to actually look at the data when you have it, and plan accordingly.

 3. Be mindful of time-based drip campaigns.

Most drip campaigns are time-based, meaning that they start on day 0 (when a person subscribes), send the next email on day 1, the next on day 3 and so on.

Drip campaigns are great because they are low maintenance–you make them once, and they run forever.

In a seasonal business, this can come back to bite you. If you’re Walmart, you wouldn’t want to send the same drip campaigns during the holiday season as back to school season.

You have a variety of solutions here. For one, you can do broadcast emails only, where everyone gets the same email regardless of when they joined. Or, you might choose to setup several different drip sequences. You might even get real fancy and put prospects on different drips depending on the time of the season.

 4. Test custom broadcast emails for the season.

High open rates require you to stand out in your subscribers’ ever-crowded inbox. One way to stand out is to put an interesting twist on something relevant to the season, such as a current event.

Here’s one from Handy themed around Valentines Day.

  Of course, there’s no guarantee that this tactic will work–that’s why we test things.

 5. Offer useful content pre-season.

Remember when we asked our customers all those questions about what caused them to buy? Well, chances are there was some sort of research they did ahead of time.

One way to stand out from the competition is to offer your subscribers value-add content when you know they are in the buying process.

Bellhops, a startup that makes moving easy, creates city guides and other moving-related content that they distribute via email. They know that people only move at most once per year, usually around summer, but they can establish brand reputation and credibility long before the move.

  Tracking the ROI of these emails isn’t as straightforward as tracking ROI on transactional emails. However, there are some content marketing analytics best practices that you can use to triangulate whether this tactic is working or not.

 6. Pay attention to segmentation.

Email segmentation can be extremely powerful. In fact, Ascend2 ranked it as the 2nd most email marketing call to action.

  There are already some ways your business can segment your email base, including:

where the subscriber is in a sales funnel,

how often the subscriber interacts with your emails,

how big of a purchaser the subscriber is,

what pages your subscribers visit.

And while the list goes on, the effectiveness of your segmentation typically diminishes the more nitty gritty you get. So make sure to stick to the segmentation that you think will drive the most results.

In a seasonal business, a powerful segment can be what time of year that subscriber joined. Or, what did that subscriber purchase at the start of last season? Are there pages your subscribers are visiting that signal pre-purchase intent?

William Griggs is the founder of VirtualRealityRental.co – a startup that allows event organizers to the book include virtual reality gear at events. He found segmenting his subscriber base by geographic region to be highly impactful.

He says, “The seasonality of our business is on a market-by-market basis. “In the summer event professionals look for cooler climates to host their events. On the flipside, in the winter event professionals look for warmer climates to host their events.” For Griggs, segmentation is simply a matter of creating cold and warm segments and emailing

Come up with a few hypotheses and test them, without getting so overcomplicated that it’s too much to manage.

 7. Plan everything ahead of time.

More important than any single tactic, is to plan your campaigns far in advance.

Why? Simply put, things get crazy during the season. When seasonal businesses are in full swing, you should be in full execution mode. You should not plan on doing customer discovery or brainstorming new tactics during the rush of things.

Far ahead of your season’s start, you should make sure to layout all tasks you need to do to be ready. Things to get done ahead of time include, but are not limited to:

Creatives

Automation

A/B tests to run

Revenue forecasts

Monitoring plans

High, low and fairway scenarios

Estimate how much time all of these will take, add a healthy 30% buffer, and back out to when you need to start planning. That way you can focus 100% of your effort on execution when things ramp up.

 Related posts

7 Important Lessons for Using Google Analytics After Scaling Upwards

Social Customer Service Trends to Watch

The post How to Succeed at Email Marketing in Seasonal Businesses appeared first on GetResponse Blog - Online Marketing Tips.

[juudgeblog]

Morning Docket: 01.03.18

* Roy Moore’s lawyer — you know, Richard Jaffe, the Jewish one — is a “passionate supporter” of Senator-elect Doug Jones, and raised and donated money for his Senate campaign before voting for him in the Alabama special election. [Washington Examiner]

* Eversheds Sutherland celebrated the new year by announcing a merger with a Dutch affiliate firm, composed of eight partners and 32 lawyers across two offices. It’ll be known as Eversheds Sutherland Netherlands once the acquisition is complete. [American Lawyer]

* Speaking of mergers, Ballard Spahr celebrated the new year by completing its combination with Lindquist & Vennum. Ballard Spahr will retain its name, and the new firm will have 650 lawyers across 15 offices in the U.S. [Big Law Business]

* The former head of alumni relations for Chicago’s John Marshall Law claims in a new lawsuit that he was fired due to the school’s bias against older male employees. He alleges that Dean Darby Dickerson is trying to “eliminate the employment of men, and particularly older men.” [Law360 (sub. req.)]

* “If you’re too busy to follow this advice, you should follow this advice.” Try this New Year’s resolution on for size: take better care of yourself with these stress management tips. [Law.com] Morning Docket: 01.03.18 syndicated from http://ift.tt/2vKNZDn

[junker-town]

The 2018 Olympics’ breakout hockey star will be 17-year-old Swedish defenseman Rasmus Dahlin

The likely No. 1 overall pick in the 2018 NHL Draft will give fans a preview in Pyeongchang.

There will be at least one NHL superstar competing at the Winter Olympics in Pyeongchang. Rasmus Dahlin may be just 17 years old and several months away from being the No. 1 overall pick in the 2018 NHL Draft, but the precocious Swedish defenseman has already made his first Olympic roster.

There won’t be a more exciting player in the tournament.

Yes, the Olympic Athletes from Russia team will have KHL stars like Ilya Kovalchuk. Team USA will have Brian Gionta and everyone’s favorite waiver claim Mark Arcobello. Canada will have Derek Roy, Rene Bourque, and Wojtek Wolski. These are guys you’ve probably heard of.

But now that Dahlin has officially made Sweden’s roster, it’s possible we look and remember this as his tournament. We won’t recall how lame it was that the NHL didn’t send its best to represent the world. We’ll celebrate how, in their place, we were treated to a three-week sneak peek of the best defenseman of his generation. And how awesome that was.

Dahlin has the potential to make that kind of impact in Pyeongchang. He’s already playing among men in Sweden, where he’s playing a key role for Frolunda HC in the SHL. He recently looked exceptional at the World Juniors, where Sweden won the silver medal. It’s hard to envision anyone else having their name called first by Gary Bettman at the draft in June.

Watch TSN analyst Ray Ferraro look almost dumbfounded trying to find the describe what it was like watching Dahlin for the first time.

Ray Ferraro är skapligt taggad på Rasmus Dahlin. Hela intervjun i Nattens NHL, 5.40 in.https://t.co/paswWHjonNhttps://t.co/fXFw9SonDb http://pic.twitter.com/HoJEsO2PJK

— Jonatan Lindquist (@Lindquistik) November 1, 2017

You can experience that, too!

This is the kind of over-the-top praise that usually elicits eye rolls around the hockey community, but not with Dahlin. Ferraro says Dahlin reminded him of the legendary Niklas Lidstrom? Well, Lidstrom himself agreed, and offered Brian Leetch as another comp. You know, just a couple of Hall of Famers. If anything, Dahlin is seemingly a combination of these traits, a type of defenseman we’ve never quite seen before.

It’ll be impossible not to notice Dahlin whenever he’s on the ice. That was often the case at World Juniors, and while the level of competition will be higher with older, more experienced players in Pyeongchang, Dahlin’s combination of skating and puck handling from the back end will be unmatched.

These Olympics were never going to be short on great stories with so many new players sharing in the Olympic dream. The fun of a ragtag American team taking on a bunch of Russian superstars nearly 40 years after the Miracle on Ice wouldn’t be lost on anyone. The wide open nature of the tournament will undoubtedly lend itself to some incredible moments.

But the star power will be seriously lacking compared to past Olympics that had Sidney Crosby, Alex Ovechkin, Patrick Kane, Henrik Lundqvist, and others taking center stage for their teams. Outside of Russia, which has a bunch of KHL stars to turn to, most of these rosters are made up of players who never dreamed of playing in an event like this. Nobody will doubt the passion and intensity of the players involved, but the talent level clearly won’t be the same.

Dahlin will be, in so many ways, the exception to the rule in Pyeongchang. He’s going to be the youngest player in the tournament. He’s going to be in the NHL very soon. And he’s going to be the most talented player there. You won’t want to miss it.

[josephquinn]

Morning Docket: 01.03.18

* Roy Moore's lawyer -- you know, Richard Jaffe, the Jewish one -- is a "passionate supporter" of Senator-elect Doug Jones, and raised and donated money for his Senate campaign before voting for him in the Alabama special election. [Washington Examiner] * Eversheds Sutherland celebrated the new year by announcing a merger with a Dutch affiliate firm, composed of eight partners and 32 lawyers across two offices. It'll be known as Eversheds Sutherland Netherlands once the acquisition is complete. [American Lawyer] * Speaking of mergers, Ballard Spahr celebrated the new year by completing its combination with Lindquist & Vennum. Ballard Spahr will retain its name, and the new firm will have 650 lawyers across 15 offices in the U.S. [Big Law Business] * The former head of alumni relations for Chicago's John Marshall Law claims in a new lawsuit that he was fired due to the school's bias against older male employees. He alleges that Dean Darby Dickerson is trying to "eliminate the employment of men, and particularly older men." [Law360 (sub. req.)] * "If you're too busy to follow this advice, you should follow this advice." Try this New Year's resolution on for size: take better care of yourself with these stress management tips. [Law.com] Morning Docket: 01.03.18 published first on http://personalinjuryattorneyphiladelphia.blogspot.com/

[brainitec]

Here's What Industry Insiders Say About Digital Marketing

Digital marketing is a team effort everyone in the team has a different role to play. The techniques and the strategies associated with digital marketing contribute differently and the entire team has to work in a disciplined manner for a common goal. Click to find out Best Digital marketing company in Pune.

 The digital entrepreneurs and industry insiders have put up an enormous impact on digital marketing services. Let's see what the industry insiders like Michael Sharkey, Becca Lindquist, and Tyson Quicksay say about Digital marketing.

 The co-founder and CEO of Autopilot, Michael Sharkey says that the digital market is revolutionized by selling cloud services to the customers which helps the marketers to decide which application to use to make purchase decisions. It has become much secured to store, manage and process the data for digital marketing.

Specifically, the global public cloud service market has seen remarkable growth of about 35% in the year 2018.

According to Becca Lindquist, Head of new businesses ‘Heap”, the online business persons should market their services like the year they are in. She also says that marketers do not find the customers for the products and services but find out the products and services required by the customers. There are many consumers who are expecting a consistent experience in this digital industry.

A founder and CEO of  “Instapage” Tyson Quick says that Digital marketing has made huge signs of progress as many companies can now individually offer the entire marketing technology suite of tools to the customers. The trends in marketing have changed to a large extent.

The director of Content Marketing at Segment Mr. Brent Summers in his recent interview said that today the condition of marketing technology is a mess as it is facing a proliferation of tools in the past few years. He says that the content is the hero of digital marketing. As according to him the consumers absorbs the content before making any purchasing decision. He emphasizes on to produce quality content instead of depending on fragmented tools available.

The head of digital marketing at Prezi Mr. Harley Butler says that the concept of big data helps in understanding the demands of the clients and it also determines the preferences and the behavioral trends of the customers. He also says that now the digital marketing is capable of synthesizing the data into actionable marketing techniques. He added that it has started to pay from an ROI’s perspective. Improve your websites organic ranking by SEO Company in Pune.

The world of digital marketing going through many changes and alterations and finding tools and tricks for digital marketing has become very easy just by keeping ourself up-to-date with the opinions and observations of the leading industry insiders in the field of digital marketing

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