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In a Single Wei Inset Patent Application Publication Aug US 20150217131A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0217131 A1 Titova et al. (43) Pub. Date: Aug. 6, 2015 (54) TERAHERTZ PULSE RADATION IN Publication Classification TREATING SKINDSORDERS (51) Int. Cl. (71) Applicants: The Governors of the University of A6IN5/06 (2006.01) Alberta, Edmonton (CA); The (52) U.S. Cl. University of Lethbridge, Lethbridge CPC ......... A61N5/0616 (2013.01); A61N 2005/066 (CA) (2013.01) (72) Inventors: Lyubov Titova, Edmonton (CA); Frank Hegmann, Edmonton (CA); Olga (57) ABSTRACT Kovalchuk, Lethbridge, (CA) (21) Appl. No.: 14/615,153 The disclosure provides methods for the treatment of skin disorders through the use of minimally invasive terahertz (22) Filed: Feb. 5, 2015 radiation. The method includes exposing skin cells to tera hertz radiation in amount Sufficient to modulate gene expres Related U.S. Application Data sion in the skin cells. The modulation of gene expression then (60) Provisional application No. 61/936,627, filed on Feb. results in a reduction of the disease state or aspects thereof in 6, 2014. the exposed skin cells. S.. R S S. & S. S. S. S. & S. S. S.s S ŠS. S.S. ^x S.S. & S.N SS. S.S S S. S S S S R S. Ski SS 8 in a single wei inset Patent Application Publication Aug. 6, 2015 Sheet 1 of 60 US 2015/0217131 A1 º?%-?.- & & cy Figure 1A Figure 1B Figure 1C Patent Application Publication Aug. 6, 2015 Sheet 2 of 60 US 2015/0217131 A1 Staturn E. S as Figure 1D S S. S S. S S.w S. & Š S s S. s &S. S. S; sS. S.S S.S. S. S S. S& S S S S. SS. Ski SS 8 in a single wei insert Figure 1E Patent Application Publication Aug. 6, 2015 Sheet 3 of 60 US 2015/0217131 A1 Down-regulated genes p-regulated genes THz pulse Tiz pulse energy at 1,0 energy O. 3-8-3-3-3s UWA pulse energy (e. 0.024 Figure 2 is sists & 88s six prisis sersy Šiš Kise 88ty Figure 3A Patent Application Publication Aug. 6, 2015 Sheet 4 of 60 US 2015/0217131 A1 $88. S & S. & 888 &&&. sww.xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx Naa | s xxi-xxxx &x-sa waxx SS SS s SSS S& S. % Figure 3B S 8 : S S8 8 : six ×××××××××××××××××××××××××××××××××××××××××××××××× ---------- .33%;#####23% Figure 3C Patent Application Publication Aug. 6, 2015 Sheet 5 of 60 US 2015/0217131 A1 Log 2 fold Entrez Gene SWmbol Chande p-value Gene ID Definition PREDICTED: Homo sapiens similar to Beta-defensin 2 precursor LOC728454 -4.O29 1.1E-06 728454. (BD-2) DEFB4 -3.975 5.3E-32 1673 Homo Sapiens defensin Homo sapiens DNA-damage DDT4 -3.353 4.8E-35 inducible transcript 4 (DDT4) Homo sapiens small proline-rich SPRR3 -2.467 4.8E-35 protein 3 (SPRR3) Homo sapiens small proline-rich SPRR2A -2.46 4.8E-35 protein 2A (SPRR2A) LCN2 -2.136 6.1E-09 Homo Sapiens lipocalin 2 (LCN2 Homo sapiens late cornified LCE3E - 1835 2.6E-11 353145 envelope 3E (LCE3E) Homo sapiens matrix MMP3 -1.83O 6.2E-04 4314 metallopeptidase 3 (stromelysin 1 IL1A -1.765 6.4E-15 3552 Homo Saoiens interleukin 1 Homo sapiens S100 calcium S100A7A - 1763 4.6E-32 binding protein A7A (S100A7A Homo sapiens sialic acid SIAE -1.7O6 2.6E-11 54414 acetylesterase (SAE) Homo sapiens dehydrogenase/reductase (SDR DHRS9 - 1673 1.8E-05 1070 family) member 9 (DHRS9) DEFB103A - 1641 6.3E-04 55894 Homo sapiens defensin PLA2G4D - 1606 2.0E-17 283748 Homo sapiens phospholipase A2 Homo sapiens late cornified LCE3D -1.498 8.7E-06 84648 envelope 3D (LCE3D Homo sapiens tribbles homolog 3 TRIB3 - 1497 1.8E-09 57761 (Drosophila) (TRIB3) Homo Sapiens Secretory leukocyte SLP - 1.457 3.2E-27 6590 peptidase inhibitor (SLP) Homo sapiens immediate early IER3 - 1420 2.0E-10 887O response 3 (IER3) VL - 1.416 4.4E-19 3713 Homo sapiens involucrin (IVL) Homo sapiens stanniocalcin 1 STC1 -1.410 4.3E-29 6781 (STC1) Homo sapiens S100 calcium S100A12 -1408 4.OE-06 6283 binding protein A12 (S100A12) Homo sapiens small proline-rich SPRR2B -1405 14E-18 67O1 protein 2B (SPRR2B) CNFN -1405 7.6E-08 84518 Homo sapiens cornifelin (CNFN) ATP2A - 1363 2.6E-26 479 Homo sapiens ATPase Homo sapiens basic helix-loop BHLHB2 - 1.355 1.7E-15 8553 helix domain containing Figure 4 Patent Application Publication Aug. 6, 2015 Sheet 6 of 60 US 2015/0217131 A1 Log 2 fold Entrez Gene symbol change p-value gene ID Definition Homo sapiens lymphocyte antigen LY6G6C - 1.316 2.6E-06 80740 6 complex Homo sapiens AP2 associated AAK1 - 1.288 7.2E-18 22848 kinase 1 (AAK1) Homo sapiens late cornified LCE3A - 1.281 2.8E-O3 353142 envelope 3A (LCE3A) Homo sapiens chloride intracellular CLIC3 - 1.274 1.1E-18 9022 channel 3 (CLIC3) Homo sapiens small proline-rich SPRR2D - 1.274 4.6E-24 6703 protein 2D (SPRR2D) Homo sapiens small proline-rich SPRR1B -1.255 1.1E-23 6699 protein 1B (cornifin) (SPRR1B) Homo sapiens methylenetetrahydrofolate dehydrogenase (NADP+ MTHFD2 -1.253 1.8E-14 10797 dependent) 2 Homo sapiens ERBB receptor ERRF1 - 1.249 2.2E-08 542O6 feedback inhibitOr 1 (ERRF1 KRT78 196374 Homo sapiens keratin 78 (KRT78) Homo sapiens Ly1 antibody LYAR 55646 reactive homolog (mouse) (LYAR) Homo sapiens dual specificity DUSP1 1843 phosphatase 1 (DUSP1) Homo sapiens KIAA1199 KIAA1199 57214 (KIAA1199) Homo sapiens small proline-rich protein 2C (pseudogene) SPRR2C 6702 (SPRR2C) Homo sapiens zinc finger protein ZFP36 7538 36 Homo sapiens kallikrein-related KLKO 5655 peptidase 10 (KLK10) Homo sapiens rhofrac guanine nucleotide exchange factor (GEF)2 ARHGEF2 91.81 ARHGEF2 PRSS27 - 1.174 2.3E-06 83886 Homo Sapiens protease Homo sapiens DNA-damage DDT3 inducible transcript 3 (DDIT3) Homo sapiens arachidonate 12 ALOX12B 242 lipOXVOenase CRYAB - 1155 2.2E-O4 1410 Homo Sapiens Crystallin CD2O7 -1.111 8.7E-04 50489 Homo Sapiens CD2O7 molecule TUBB4C) - 1.103 10E-15 56604 Homo sapiens tubulin TUBB3 - 1.101 2.6E-03 10381 Homo sapiens tubulin Homo sapiens partner of NOB1 PNO1 - 1.095 2.1E-18 56902 homolog (S. cerevisiae) (PNO1) Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 7 of 60 US 2015/0217131 A1 Log 2 fold Entrez Gene symbol change p-value gene ID Definition TUBA4A - 1,090 1.1E-08 7277 Homo sapiens tubulin Homo sapiens corneodesmosin CDSN - 1.087 21E-O6 O4 (CDSN) Homo sapiens MAX dimerization MXD1 - 1086 2.7E-O7 4084 Orotein 1 (MXD1 KRT34 Homo sapiens keratin 34 (KRT34) Homo sapiens homocysteine HER PUD1 inducible Homo sapiens protein phosphatase PPP1R3C Homo sapiens galectin-related HSPC159 Orotein (HSPC159 Homo sapiens glutathione S GSTT2 653689 transferase theta 2 (GSTT2) Homo sapiens SH2B adaptor SH2B3 10019 protein 3 (SH2B3) PLA2G4B 8681 Homo sapiens phospholipase A2 Homo sapiens glutathione S transferase theta 2B GSTT2B 653689 denefoSeudocene) (GSTT2B Homo sapiens chromosome 1 open C1 Orf63 reading frame 63 (C1orf63) Homo sapiens ArfGAP with dual ADAP2 PH domaiS 2 (ADAP2 PRSS3 5646 Homo sapiens protease CALE2 794 Homo sapiens calbindin 2 (CALB2) Homo sapiens cytidine deaminase CDA 978 (CDA) Homo sapiens CD24 molecule CD24 1OO 133941 (CD24) P3 5266 Homo sapiens peptidase inhibitor 3 Homo sapiens dual specificity DUSP5 1847 phosphatase 5 (DUSP5) Homo sapiens serpin peptidase SERPINB13 5275 inhibitor Homo sapiens apolipoprotein B APOB (including Ag(x) antigen) (APOB) Homo sapiens transglutaminase 3 TGM3 (E polypeptide Homo sapiens NGF-A binding protein 2 (EGR1 binding protein 2) NAB2 NAB2 CD55 1604 Homo sapiens CD55 molecule HIST1H1C 3OO6 Homo sapiens histone cluster 1 SBSN 374897 Homo Sapiens Suprabasin (SBSN Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 8 of 60 US 2015/0217131 A1 Log 2 fold Entrez Chande O-Value Gerre ID Definition Homo sapiens polymerase (RNA) III (DNA directed) polypeptide B POLR3B -0.942 8.7E-13 55703 (POLR3B) Homo sapiens zinc finger protein ZFP36L1 -0.936 7.5E-05 677 36 Homo sapiens family with FAM25G -0.929 9.2E-09 || 100133093 sequence similarity 25 CRNN -0.922 3.3E-03 49860 Homo Sapiens Cornulin (CRNN Homo sapiens CDC-like kinase 1 CLK1 1195 (CLK1) Homo sapiens DnaJ (Hsp40) DNAJB9 -0.916 6.2E-09 489 homoloc Homo sapiens ras homolog gene RHOD 29984 family Homo sapiens NOP16 nucleolar NOP16 -0.907 3.1E-14 51491 Orotein homolod (weast) (NOP16 NeNP Tools-O.904 9.4E-04 to 4860 HomoOhOSohorylase sapiens nucleoside(NP Homo sapiens secreted LY6/PLAUR domain containing 1 SLURP1 -0.904 1.9E-15 57152 SLURP serieneSERPINB4 loselaete-0.902 2.1E-12 6318 inhibitOrHomo sapiens Serpin peptidase Homo sapiens serine peptidase SPINK6 404203 inhibitor Homo sapiens dyskeratosis DKC 1736 Concenita 1 Homo sapiens ATP-binding ABCE1 -0.896 1.7E-12 6059 CaSSette Homo sapiens metallothionein 1G MT1G -0.895 14E-10 4495 (MT1G) Homo sapiens KIAA0020 KIAAOO2O -0893 4.1E-14 9933 (KIAA0020) BTG2 -0.893 3.OE-04 7832 Homo sapiens BTG family Homo sapiens small proline-rich SPRR4 -O.892 3.9E-05 163778 protein 4 (SPRR4) Homo sapiens hypothetical protein HSPC111 -O.887 1.1E-12 51491 HSPC111 (HSPC111) Homo sapiens LY6/PLAUR domain LYPD5 -O.883 1.5E-06 284348 containing 5 (LYPD5) Homo sapiens coiled-coil domain CCDC86 -O.867 6.5E-05 7908O containing 86 (CCDC86) Homo sapiens small proline-rich SPRR2F -O.862 6.2E-11 6705 protein 2F (SPRR2F) KRT8O -O.857 1.1E-05 1445O1 Homo sapiens keratin 80 (KRT80) Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 9 of 60 US 2015/0217131 A1 fold Entrez Gene SVmbol Chande p-value Cere ID Definition Homo sapiens signal-induced proliferation-associated 1 like 2 SPAL2 -0.857 5.6E-07 57568 SPA12 TUBB2A -O.854 1.6E-10 7280 Homo sapiens tubulin Homo sapiens Serpin peptidase SERPINB7 -0853 1.6E-13 8710 inhibitOr PRSS2 6.6E-06 5645 Homo sapiens protease Homo sapiens family with FAM43A 2.3E-12 131583 sequence similarity 43 Homo sapiens carbohydrate (N-
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