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 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.

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Log 2 fold Gene SWmbol Chande p-value Gene ID Definition PREDICTED: Homo sapiens similar to Beta- 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 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 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 () 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 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- acetylglucosamine 6-O) CHST7 4.5E-08 56548 Sulfotransferase 7 Homo sapiens interferon stimulated SG20 3.7E-10 3669 exonuclease Cene 20kDa (ISG20 Homo sapiens arachidonate ALOXE3 58E-04 59344 lipoxygenase 3 (ALOXE3) Homo sapiens 6-phosphofructo-2- PFKFB3 5.7E-13 5209 kinase/fructose-2 TUBB2C -O.839 1.2E-O2 10383 Homo sapiens tubulin Homo sapiens glutathione GPX3 -0.839 1.1E-03 2878 OerOxidase 3 (plasma) (GPX3 Homo sapiens C16orf56 4.5E-02 8O152 open reading frame 56 (C16orf56) CYP4F22 5.2E-04 12641 O Homo sapiens cytochrome P450 Homo sapiens cysteinyl-tRNA CARS 9.8E-06 833 Synthetase (CARS

PsmorePSMD12 loses-0.826 54E-09 578 HomoOOSOe sapiens proteasome

PPPiasaPPP1R 15A Toes-O.826 6.1E-11 23645 Homo1 sapiens protein phosphatase Homo sapiens chromosome 6 open C6Orf66 3.6E-O7 29 O78 reading frame 66 (C6orf66) Homo sapiens fucosyltransferase 3 (galactoside 3(4)-L- FUT3 1.4E-O2 2525 fucosyltransferase SCNN1B 6.5E-07 6338 Homo sapiens sodium channel Homo sapiens clock homolog CLOCK 2.2E-03 95.75 (mouse) (CLOCK) Homo sapiens small proline-rich SPRR2E 1.3E-12 6704 protein 2E (SPRR2E) Homo sapiens solute carrier family SLC5A1 18E-04 6523 5 (Sodium/glucose cotransporter) Homo sapiens transmembrane 7 TM7SF2 7.4E-04 7108 superfamily member 2 (TM7SF2) Homo sapiens Spermidine SRM 3. E-10 6723 SVnthase (SRM Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 10 of 60 US 2015/0217131 A1

Log 2 fold Entrez Gene symbol change p-value gene ID Definition Homo sapiens forkhead box Q1 FOXO1 -O.8O3 6.2E-05 94234 (FOXO1) Homo sapiens Seven in absentia SAH2 -0.796 3.5E-10 6478 homolog 2 (Drosophila) (SIAH2) Homo sapiens UDP-glucose ceramide glucosyltransferase UGCG -0.796 5.2E-03 7357 (UGCG) Homo sapiens transmembrane TMEM79 -O.794 7.1E-O3 84.283 protein 79 (TMEM79) Homo sapiens DEAD (Asp-Glu-Ala DDX21 -O.792 3.OE-09 91.88 ASO) box polvoeotide 21 (DDX21 Homo sapiens v-fos FBJmurine osteosarcoma viral oncogene FOS -0.789 8.3E-06 2353 homolog (FOS) Homo sapiens methylthioadenosine MTAP -O.787 2.3E-09 4507 phosphorylase (MTAP) Homo sapiens peptidase inhibitor P15 -O.786 1.7E-O2 51050 15 (P15 Homo sapiens S100 calcium S1 OOP -O.781 7.4E-O3 6286 binding protein P (S100P) Homo sapiens transmembrane TMEM222 -O.778 14E-O4 84O65 protein 222 (TMEM222) Homo sapiens centromere protein CENPT -O.777 12E-O2 8O152 T (CENPT) Homo sapiens chemokine (C-C CCL20 -0.774 11E-O2 6364 motif) ligand 20 (CCL20) Homo sapiens family with FAM25C -O.768 6.1E-05 644O54 sequence similarity 25 Homo sapiens chromosome 9 open C9Orf169 -O.768 2.5E-03 375791 readind frame 169 (C9orf169 Homo sapiens dual oxidase DUOXA1 -O.767 1.7E-O4 90527 maturation factor 1 (DUOXA1) Homo sapiens immediate early IER5L -0.766 2.5E-06 389792 response 5-like (IER5L) Homo sapiens spinster homolog 2 SPNS2 -O.765 2.9E-09 124976 (Drosophila) (SPNS2) ILF9 -O.765 2.3E-O7 563OO Homo Sapiens interleukin 1 famil RHCG -O.757 3.9E-03 51458 Homo Saoiens Rh famil Homo sapiens hypothetical protein LOC10O128288 -0.748 1.OE-06 100 128288 . LOC100 128288 (LOC100 128288) Homo sapiens salt-inducible kinase SK1 -O.746 3.2E-03 15OO94 1 (SK1) Homo sapiens WAP four-disulfide WFDC5 -O.746 2.OE-03 149708 Core domain 5 (WFDC5 Homo sapiens DEAD (Asp-Glu-Ala DDX10 -O.746 2.4E-O7 1662 Asp) box polypeptide 10 (DDX10) Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 11 of 60 US 2015/0217131 A1

fold Entrez Gene SWimbol Chande p-value Gene ID Definition Homo sapiens cyclin-dependent CDKN1B 4.6E-04 1 O27 kinase inhibitor 1B (p27 Homo sapiens LY6/PLAUR domain LYPD3 9.1E-03 27O76 containing 3 (LYPD3) LPG 1.OE-02 9388 Homo Sapiens lipase

correC1 Orf1 16 Tozai-O.741 2.4E-O2 79 098 Homoreadind sapiens frame 116chromosome (C1 orf1 16 1 open Homo sapiens transferrin receptor 7.OE-05 7037 (p90 Homo sapiens threonyl-tRNA 7.OE-09 6897 synthetase (TARS) 5.6E-03 6415 Homo Sapiens Selenoorotein W Homo sapiens mitochondria associated protein involved in granulocyte -macrophage colony-stimulating factor signal transduction

Madmas -O.733 3.8E-05 51025 Madmas HIST2H2AC 6.7E-O7 8338 Homo sapiens histone cluster 2 L1F10 3.2E-O2 84639 Homo sapiens interleukin 1 family Homo sapiens MAK16 homolog (S. MAK16 2.2E-04 84549 cerevisiae) (MAK16) Homo sapiens NOP2/Sun domain NSUN2 1.3E-03 54888 family HIST2H2AA3 15E-09 8337 Homo Sapiens histone cluster 2 RNASE7 3.7E-03 84659 Homo sapiens ribonuclease Homo sapiens arginine AVP 4.5E-03 60370 vasopressin-induced 1 (AVP) Homo sapiens GTP binding protein GTPBP4. 1.3E-05 23560 4 (GTPBP4. 7.4E-03 705 Homo sapiens bystin-like (BYSL) Homo sapiens kallikrein-related 1.1E-O2 5650 peptidase 7 (KLK7) Homo sapiens ribosomal RNA processing 15 homolog (S. 2.9E-06 51 O18 Cere Visiae) (RRP15

RNasRNF39 loes,-0.697 6.4E-O6 8O352 39Homo (RNF39 sapiens ring finger protein

GRWD1grwol loss,-0.697 4.7E-03 83743 Homorepeat sapienscontainind glutamate-rich 1 (GRWD1 WD Homo sapiens BCL2/adenovirus E1B 19kD interacting protein like BNPL -0.694 3.2E-O2 149428 (BNPL) Homo sapiens SH3 domain binding glutamic acid-rich protein like 3 SH3BGRL3 -0.691 2.4E-08 83442 (SH3BGRL3) Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 12 of 60 US 2015/0217131 A1

Log 2 fold Entrez Gene SVmbol Chande p-value Gene ID Definition Homo sapiens DIM1 dimethyladenosine transferase 1 DMTL 3.7E-07 27292 like (S. cerevisiae) (DIMTL) Homo sapiens RUN domain RUNDC3A 3.5E-03 10900 containing 3A (RUNDC3A) Homo sapiens cysteine-rich C NICE-1 1.2E-O2 54544 terminal 1 (CRCT1) Homo sapiens tyrosine 3 monooxygenase/tryptophan 5 monooxygenase YWHAE 2.5E-07 7531 activation protein Homo sapiens open reading frame 137 C10orf137 1.3E-05 26098 (C10orf137) Homo sapiens PDZK1 interacting PDZK1 P1 2.4E-03 1 O158 protein 1 (PDZK1 IP1) Homo sapiens mitochondrial MRPL12 5.7E-O3 6182 ribosoma Orotein L12 (MRPL12 oars Homo sapiens dual specificity DUSP6 -0.679 5.9E-03 1848 phosphatase 6 (DUSP6 Homo sapiens Serpin peptidase SERPINB3 5.9E-09 631 7 inhibitor Homo sapiens Sphingomyelin SMPD3 OE-05 55512 phosphodiesterase 3 DEFB1 3.9E-05 1672 Homo sapiens defensin RASD1 1.6E-04 51655 Homo sapiens RAS Homo sapiens Solute carrier family SLC 15A1 8.9E-03 6564 15 (oligopeptide transporter) Homo sapiens SERTA domain SERTAD2 5.7E-09 9792 containing 2 (SERTAD2) Homo sapiens solute carrier family SLC20A1 1.7E-O4 6574 20 (phosphate transporter oes Homo sapiens S100 calcium S1 OOA11 -0.663 1.9E-04 6282 bindind protein A11 (S100A11 oese Homo sapiens telomeric repeat TERF2P -0.662 4E-O7 54386 bindind factor 2 Homo sapiens chromosome 16 C16orf30 8.7E-04 79652 open reading frame 30 (C16orf30) Homo sapiens SDA1 domain SDAD1 1.7E-04 55153 containing 1 (SDAD1) Homo sapiens G patch domain GPATCH4 4.5E-02 54865 containing 4 (GPATCH4) Homo sapiens transmembrane TMEM166 6.1E-05 84.141 protein 166 (TMEM166) Homo sapiens kinesin family KF13B 1.5E-O2 233O3 member 13B (KF13B JUN -0.654 5.1E-O6 3725 Homo sapiens jun oncogene (JUN) Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 13 of 60 US 2015/0217131 A1

Log 2 fold Entrez Gene SWmbol Chance p-value Gene ID Definition Homo sapiens tissue factor TFP2 -O.652 pathway inhibitor 2 (TFPI2) Homo sapiens annexin A3 ANXA3 -O.652 (ANXA3) Homo sapiens K(lysine) KAT2B -O.65 acetyltransferase 2B (KAT2B) Homo sapiens PMM2 -O.651 phosphomannomutase 2 (PMM2) Homo sapiens nucleolar protein 11 NOL11 -O.65 NOL11 Homo sapiens calmodulin regulated spectrin-associated CAMSAP1L1 -0.65 Orotein 1-like 1 Homo sapiens proliferation PA2G4 -O.650 asSociated 2G4 Homo sapiens LTV1 homolog (S. LTV1 -O.650 Cerevisiae) (LTV1 Homo sapiens deoxyribonuclease DNASE1L2 -0.648 1775 |-like 2 (DNASE1L2) Homo sapiens cathepsin L2 CTSL2 -0.648 1515 (CTSL2) Homo sapiens transmembrane TMEM106A -O.647 13277 protein 106A (TMEM106A) Homo sapiens exosome EXOSC6 -O.647 118460 component 6 (EXOSC6) Homo sapiens NMDA receptor NARG1 -0.646 8O155 redulated 1 (NARG1 Homo sapiens RNA binding motif RBM25 -O.645 protein 25 (RBM25) Homo sapiens serine peptidase SPINK5 -0.643 inhibitor Homo sapiens family with sequence similarity 62 (C2 domain FAM62C -O.643 3.7E-02 83850 Containino Homo sapiens intermediate IFFO2 -O.642 126917 filament family orphan 2 (IFFO2) Homo sapiens prostaglandin PTGR2 -O.642 145482 reductase 2 (PTGR2) Homo sapiens three prime repair TREX2 -0.642 11219 exonuclease 2 (TREX2) Homo sapiens IGF-like family |GFL2 -O.639 14792O member 2 (IGFL2) Homo sapiens mRNA turnover 4 MRTO4 -0.639 51154 homolod (S. cerevisiae) (MRTO4 Homo sapiens fatty acid binding protein 5 (psoriasis-associated) FABP5 -O.638 1.9E-04 2171 (FABP5) Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 14 of 60 US 2015/0217131 A1

Log 2 fold Entrez Gene symbol change p-value gene ID Definition Homo sapiens phosphoribosyl pyrophosphate amidotransferase PPAT -0.638 1.7E-04 54.71 PPAT Homo Sapiens karyopherin alpha 4 KPNA4 -0.638 3840 (importin alpha 3) (KPNA4) Homo sapiens tRNA methyltransferase 6 homolog (S. TRMT6 -0.637 51605 cerevisiae) (TRMT6) Homo sapiens nuclear transcription NFXL1 -0.635 152518 factor Homo sapiens non-specific cytotoxic cell receptor protein 1 NCCRP1 -0.635 342897 homoloc Homo sapiens kallikrein-related KLK5 -O.634 peptidase 5 (KLK5) Homo sapiens nuclear factor (erythroid-derived 2)-like 3 NFE2L3 -0.634 (NFE2L3) Homo sapiens exosome EXOSC9 -0.632 Component 9 (EXOSC9 NEFH -0.63 Homo Sapiens neurofilament Homo sapiens low density lipoprotein receptor (familial LDLR -O.625 3949 hypercholesterolemia) Homo sapiens INO80 complex NO8OC -0.625 125476 subunit C (NO80C) Homo sapiens feline leukemia virus FLVCR2 -0.625 55640 Subdroup C Cellular receptor famil Homo sapiens premature ovarian POF1B -O.624 failure Homo sapiens BCL2-associated BCLAF1 -0.623 1 (BCLAF1) Homo sapiens CCAAT/enhancer CEBPG -0.622 binding protein (C/EBP) Homo sapiens chromosome 12 C12Orf5 -0.621 open reading frame 5 (C12orf5) Homo sapiens tyrosy-DNA TDP 1 -0.619 ohoSohodiesterase 1 (TDP1 SFN -0.6.18 Homo Sapiens Stratifin (SFN Homo sapiens prostaglandin PTGS2 -0.618 1.3E-05 5743 endoperoxide synthase 2 Homo sapiens MTERF domain MTERFD1 -0.616 8.5E-06 51 OO1 containing 1 (MTERFD1) ARG1 -0.616 9.OE-03 383 Homo sapiens arginase Homo sapiens Rab RABGGTB -0.66 2.6E-06 5876 geranylgeranyltransferase Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 15 of 60 US 2015/0217131 A1

Log 2 fold Entrez Gene symbol change p-value gene ID Definition Homo sapiens hypothetical protein MGC4677 -0.613 3.9E-02 112597 MGC4677 (MGC4677) Homo sapiens tripartite motif TRIM25 -0.612 3.8E-03 77O6 containing 25 (TRIM25) Homo sapiens iduronate 2 IDS -0.608 2.6E-05 3423 Sulfatase (Hunter syndrome) (IDS) Homo sapiens WD repeat domain WDR12 -0.606 4.1E-04 55759 12 (WDR12) Homo sapiens WD repeats and SOF 1 domain containing WDSOF1 -0.603 | 1.4E-04 25879 (WDSOF1) Homo sapiens WW and C2 domain WWC -0.602 | 1.2E-O2 23286 containing 1 (WWC1) Homo sapiens MAP kinase interacting serine/threonine kinase MKNK2 0.6OO 2.2E-02 2872 2 (MKNK2) Homo sapiens secreted frizzled SFRP2 O6O2 8.3E-04 6423 related protein 2 (SFRP2) Homo sapiens aldo-keto reductase AKR1B15 O6O2 2.6E-05 44.1282 family 1 Homo sapiens procollagen C endopeptidase enhancer PCOLCE 0.602 15E-02 5118 (PCOLCE) Homo sapiens G protein-coupled GPR68 O.605 || 1.4E-04 8111 receptor 68 (GPR68) LAMA4 O.610 4.4E-22 390 Homo sapiens laminin Homo sapiens myelin basic protein MBP O.610 2.9E-02 4155 (MBP) ACYP1 O.610 6.1E-04 97 Homo sapiens acylphosphatase 1 Homo sapiens olfactomedin-like 1 OLFML.1 O610 3.6E-05 283298 (OLFML1) Homo sapiens hypothetical protein MGC 16169 O.61O 8.OE-04 93627 MGC16169 (MGC16169) Homo sapiens w-ets erythroblastosis virus E26 ETS2 0.612 15E-06 2114 oncogene homolog 2 Homo sapiens progestin and adipoCR receptor family member IV PAOR4 O618 1.3E-02 124222 (PACR4) Homo sapiens zinc finger protein ZNF627 O.619 3.9E-08 1996.92 627 (ZNF627) Homo sapiens derived PDGFC O.619 4.7E-06 56.034 growth factor C (PDGFC) Homo sapiens Src kinase associated phosphoprotein 2 SKAP2 O62O 3.8E-03 8935 (SKAP2) COL12A1 O.62O 4.8E-O7 1303 Homo sapiens collagen Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 16 of 60 US 2015/0217131 A1

Log 2 fold Erez Gene SWmbol Chande O-Value Cere ID Definition Homo sapiens zinc finger and BTB 26137 domain containing 20 (ZBTB20) Homo sapiens zinc finger protein ZNF433 O.622 163059 433 (ZNF433 Homo sapiens HCLS1 binding HS1 BP3 O.622 64342 protein 3 (HS1BP3) Homo sapiens interferon gamma receptor 2 (interferon gamma IFNGR2 O.623 3460 transducer 1 Homo sapiens transmembrane TMEM119 O.624 1.7E-10 338.773 protein 119 (TMEM119) PODN O.624 1.OE-03 127435 Homo Sapiens OOdoCan (PODN CAPN5 O.624 44E-02 726 Homo Sapiens Calpain 5 (CAPN5 Homo sapiens transforming growth TGFB3 O.625 1.OE-02 7043 factor ODZ3 O.626 2.4E-03 557.14 Homo Sapiens Odz Homo sapiens meningioma (disrupted in balanced MN1 O627 4330 translocation) 1 (MN 1) TAP1 O.629 6890 Homo sapiens transporter 1 Homo Sapiens bone marrow BST2 O.630 684 Stromal cell antiden 2 (BST2 ZDHHC14 O.630 Homo sapiens zinc finger NHBB O.631 Homo sapiens inhibin Homo sapiens family with FAM46A O.637 SeCuence Similarity 46 COL3A1 Homo sapiens collagen Homo sapiens transcription factor TCF2 12 (TCF12) Homo sapiens transducin (beta)- like 1X-linked receptor 1 TBL1 XR1 (TBL1XR1) Homo sapiens N-glycanase 1 NGLY1 NGLY1 Homo sapiens ankyrin repeat and death domain containing 1A ANKDD1A 34.8094 (ANKDD1A) Homo sapiens chromosome 2 open C2Orf64 4.93753 reading frame 64 (C2Orf64) Homo sapiens kelch domain KLHDC8B 200942 containing 8B (KLHDC8B) AXN2 8313 Homo sapiens axin 2 (conductin Homo sapiens myosin regulatory light chain interacting protein MYLIP 29, 16 MYLIP CACNB3 O.644 4.OE-04 784 Homo sapiens calcium channel Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 17 of 60 US 2015/0217131 A1

Log 2 fold Entrez Gene symbol change p-value gene ID Definition SULF1 O.645 1.8E-05 23213 Homo sapiens sulfatase 1 (SULF1) PREDICTED: Homo sapiens odd skipped related 2 (Drosophila) OSR2 O.645 2.2E-04 116039 OSR2 VCAN O.645 3.9E-05 1462 Homo Sapiens versican (VCAN Homo sapiens solute carrier family SLC4OA1 O.646 1.5E-04 3OO61 40 (iron-redulated transporter Homo sapiens aldo-keto reductase AKR1C2 0.650 8.3E-12 1646 family 1 Homo sapiens keratin 9 (epidermolytic palmoplantar KRT9 0.654 1.2E-03 3857 keratoderma) (KRT9) Homo sapiens late cornified LCE1E 0.655 3.7E-O2 353135 envelope 1E (LCE1E) Homo sapiens zinc finger and BTB ZBTB4 0.655 7.6E-O6 57659 domain containing 4 (ZBTB4) Homo sapiens basonuclin 1 BNC 1 0.658 1.3E-O2 646 (BNC1) Homo sapiens chemokine (C-X-C CXCL10 O.659 6.2E-03 3627 motif) ligand 10 (CXCL10) Homo sapiens cingulin-like 1 CGNL1 O.660 4.1E-04 84952 (CGNL1) Homo sapiens high-mobility group HMGB2 O.663 2.OE-04 3148 box 2 (HMGB2) Homo sapiens similar to solute LOC728661 0.663 1.9E-06 728661 carrier family 35 Homo sapiens sorting nexin 25 SNX25 0.666 2.3E-04 83891 (SNX25) EGFL6 0.666 3.3E-06 25975 Homo sapiens EGF-like-domain LUM O.666 5.5E-06 4O60 Homo sapiens lumican (LUM) Homo sapiens helicase with zinc HELZ O.668 8.9E-06 9931 finger (HELZ) RASL12 0.669 2.8E-O7 5285 Homo sapiens RAS-like Homo sapiens hyaluronan HAS2 O.669 2.1E-06 3O37 synthase 2 (HAS2) Homo sapiens family with FAM134B O.671 5.3E-03 54.463 secuence similarity 134 Homo sapiens angiopoietin-like 2 ANGPTL2 O.672 2.5E-04 234.52 (ANGPTL2) CYP2S1 O.672 1.2E-04 29785 Homo sapiens cytochrome P450 Homo sapiens multiple EGF-like MEGF6 O.674. 4.6E-03 1953 domains 6 (MEGF6) Homo sapiens endoplasmic reticulum aminopeptidase 2 ERAP2 O.674 2.OE-08 64 167 ERAP2 Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 18 of 60 US 2015/0217131 A1

Log 2 fold Entrez Gene symbol change p-value gene ID Definition Homo sapiens internexin neuronal NA O.675 14E-04 9118 intermediate filament protein Homo sapiens ADP-ribosylation ARL-4A O.680 7.1E-09 1O 124 factor-like 4A (ARL4A Homo sapiens sarcospan (Kras oncogene-associated gene) SSPN O.682 3.6E-05 8082 (SSPN) Homo sapiens NYN domain and retroviral integrase containing NYNRIN 0.685 4.3E-09 57523 (NYNRIN) Homo sapiens interferon regulatory RF1 O.685 1.6E-05 3659 factor 1 (IRF1) Homo sapiens alpha-2- A2M O.685 4.8E-03 2 macroglobulin (A2M) ATXN1 O.687 4.1E-09 631 O Homo sapiens ataxin 1 (ATXN1) Homo sapiens UDP-N-acetyl GALNTL4 O.688 5.9E-04 374378 aloha-D-CalactOSamine Homo sapiens tumor necrosis TNFRSF6B 0.689 4.7E-13 877 factor receptor superfamily Homo sapiens aldo-keto reductase AKR1C3 O.690 3.7E-O7 8644 family 1 COL5A1 O.691 6.2E-06 1289 Homo sapiens collagen Homo sapiens zinc finger protein ZNF827 O.692 1.6E-04 152485 827 (ZNF827) Homo sapiens G protein-coupled GPRC5C O.693 2.9E-12 55890 receptor Homo sapiens matrix-remodelling MXRA5 O.693 | 1.4E-08 25878 associated 5 (MXRA5) Homo sapiens tumor necrosis TNFSF10 O.696 || 4.1E-03 8743 factor (ligand) superfamily FBLN2 O.696 5.1 E-06 2199 Homo sapiens fibulin 2 (FBLN2) Homo sapiens regulator of G RGS4 0.696 4.3E-05 5999 Orotein Sionallino. 4 (RGS4 COL 6A 0.699 4.4E-2 1307 Homo Sapiens CollaCen Homo sapiens dermatopontin DPT O.7O1 1.OE-03 1805 (DPT) Homo sapiens glutathione peroxidase 2 (gastrointestinal) GPX2 O.703 2.7E-04 2877 (GPX2) Homo sapiens potassium voltage KCNS3 0.704 8.2E-04 3790 dated Channel Homo sapiens prostaglandin E receptor 4 (subtype EP4) PTGER4 O.704 1.9E-03 5734 (PTGER4) Homo Sapiens Scavenger receptor SCARF2 O.705 4.9E-18 91179 Class F

Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 19 of 60 US 2015/0217131 A1

Entrez Gene symbol gene ID Definition Homo sapiens alcohol ADH 1A 124 dehydrogenase 1A (class I) Homo sapiens amyloid beta (A4) APBB3 10307 precursor protein-binding CD248 57124 Homo Sapiens CD248 molecule Homo sapiens acid phosphatase 92370 like 2 (ACPL2 Homo sapiens hypothetical protein FLJ35258 284297 284297 (FLJ35258) Homo sapiens ring finger protein RNF150 57484 150 (RNF150) Homo sapiens olfactomedin-like 2A OLFML2A 1696.11 (OLFML2A) Homo sapiens kelch repeat and BTB (POZ) domain containing 11 KBTBD 992O (KBTBD11) Homo sapiens Rho GTPase ARHGAP20 57569 activating protein 20 (ARHGAP20) Homo sapiens fibroblast growth FGF11 2256 factor 11 (FGF11) Homo sapiens KIAAO182 KIAAO182 23199 (KIAAO182) REV3L 598O Homo sapiens REV3-like Homo sapiens Sin3A-associated SAP30 889 protein Homo sapiens bobby Sox homolog BBX 56987 (Drosophila) (BBX) Homo sapiens ADAM metallopeptidase with ADAMTS1 951O thrombospondin type 1 motif Homo sapiens solute carrier family SLC25A42 284.439 25 Homo sapiens REST corepressor 2 RCOR2 283248 (RCOR2) Homo sapiens protein tyrosine PPFA4 8497 phosphatase Homo sapiens aldo-keto reductase AKR1B1O 57O16 family 1 COL7A1 1294 Homo sapiens collagen Homo sapiens late cornified LCE1D 353134 envelope 1 D (LCE1D) Homo sapiens dehydrogenase/reductase (SDR DHRS13 14705 family) member 13 (DHRS13 Homo sapiens transmembrane TMEMOO O.744 2.OE-05 55273 protein 100 (TMEM100) Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 20 of 60 US 2015/0217131 A1

Log 2 fold Errez Gene symbol change p-value gene ID Definition Homo sapiens claudin 23 CLDN23 O.745 4.5E-09 137O75 (CLDN23) COL15A1 O.747 1.OE-03 1306 Homo sapiens collagen Homo sapiens SH3 and PX SH3PXD2A O.759 2.7E-35 9644 domains 2A (SH3PXD2A) Homo sapiens prostaglandin F PTGFR O.76O 1.7E-05 5737 receptor (FP) (PTGFR) Homo sapiens eg nine homolog 1 EGLN1 O.764 1.OE-06 54583 (C. elegans) (EGLN1) ELN 0.767 6.1E-05 2006 Homo sapiens elastin (ELN) Homo sapiens active BCR-related ABR 0.775 5.2E-03 29 gene (ABR) Homo sapiens dehydrogenase/reductase (SDR DHRS3 0.776 E-12 9249 family) member 3 (DHRS3) Homo sapiens sorting nexin 33 SNX33 0.777 8.3E-09 257364 (SNX33) Homo sapiens CD276 molecule CD276 O.777 9.OE-04 8O38 (CD276) Homo sapiens plasticity related LPPR4 O.778 9.8E-08 9890 ene 1 (LPPR4 Homo sapiens Rho guanine exchange factor (GEF) 16 ARHGEF16 O.778 8.OE-O6 27237 (ARHGEF16) Homo sapiens achaete-scute complex homolog 2 (Drosophila) ASCL2 O.78O 4.5E-05 43O (ASCL2) LAMA5 O.795 2.9E-03 3911 Homo sapienslaminin Homo sapiens platelet-derived PDGFRB O.795 5.5E-11 5159 growth factor receptor Homo sapiens integrator complex INTS3 O.801 2.5E-05 65123 subunit 3 (NTS3) SPRY1 O.805 2.8E-06 10252 Homo sapiens sprouty homolog 1 POSTN 0.810 1.1 E-18 10631 Homo sapiens periostin Homo sapiens deltex homolog 2 DTX2 O.812 3.1E-O3 113878 (Drosophila) (DTX2) Homo sapiens leucine rich repeat LRRC32 O814 3.8E-O6 2615 containing 32 (LRRC32) Homo sapiens family with FAM83B O.814 47E-O7 222584 sequence similarity 83 Homo sapiens protein tyrosine PTPRK 0.817 2.8E-07 5796 phosphatase FBLN1 O.819 2.3E-O6 2.192 Homo sapiens fibulin 1 (FBLN1) Homo sapiens neuron navigator 1 NAW O822 3.5E-O 89796 (NAV 1) Homo sapiens pleckstrin PHLDB2 O.826 2.6E-O 90102 homology-like domain Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 21 of 60 US 2015/0217131 A1

Log 2 fod Entrez Gene symbol change p-value gene ID Definition LAMA2 O.829 4.8E-O7 3908 Homo sapienslaminin Homo sapiens maternally expressed 3 (non-protein coding) MEG3 O844 1.7E-O6 55384 (MEG3) CYRS1 O845 1.2E-09 3491 Homo sapiens cysteine-rich Homo sapiens vang-like 2 (van VANGL2 O.854 1.3E-O8 57216 doch Homo sapiens LIM domain binding LDB2 O.86O 3.4E-O7 9079 2 (LDB2) Homo sapiens exportin 1 (CRM1 XPO1 O861 2.3E-10 7514 homolog Homo sapiens PTK7 protein PTK7 O.863 3.OE-10 5754 tyrosine Kinase 7 (PTK7 Homo sapiens PHD finger protein PHF21A O.863 2.7E-35 51317 21A (PHF21A) Homo sapiens proenkephalin PENK 0.865 4.7E-05 5179 (PENK) Homo sapiens TIMP metallopeptidase inhibitor 3 TIMP3 O867 18E-O7 7078 (TIMP3) Homo sapiens translocation associated membrane protein 2 TRAM2 O.874 2.7E-35 9697 TRAM2 Homo sapiens thrombospondin2 THES2 0.878 2.7E-35 70.58 (THBS2) Homo sapiens kelch-like 22 KLHL22 O878 4.2E-12 84861 (Drosophila) (KLHL22) Homo sapiens UDP-N- acteylglucosamine pyrophosphorylase 1-like 1 UAP1L1 O880 42E-O5 91373 (UAP1L1) Homo sapiens HLA complex P5 HCP5 O.883 1.6E-06 10866 (HCP5) Homo sapiens tripartite motif TRIM47 O890 6.2E-O8 911 O7 containing 47 (TRIM47) Homo sapiens cell division cycle 2 CDC2L6 O893 1.6E-04 23097 like 6 (CDK8-like) (CDC2L6 Homo sapiens complement factor CFB O.895 2.4E-O5 629 B (CFB) Homo sapiens IGF-like family |GFL1 0.897 1.3E-08 374918 member 1 (IGFL1) Homo sapiens cholesterol 25 CH25H O900 18E-O7 9023 hydroxylase (CH25H) Homo sapiens odd-skipped related OSR1 0.905 1.2E-11 130497 1 (Drosophila) (OSR1) Homo sapiens fibroblast growth FGFR3 O909 44E-O2 2261 factor receptor 3 (achondroplasia Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 22 of 60 US 2015/0217131 A1

Log 2 fold Entrez Gene symbol Chande p-value dene ID Definition Homo sapiens late cornified LCE1B O.914 3.8E-O7 353132 envelope 1B (LCE1B) MUC1 O.917 | 1.5E-14 4582 Homo Sapiens mucin 1 Homo sapiens ras homolog gene RHOU O.921 2.7E-35 58480 famil Homo sapiens adenomatosis polyposis coli down-regulated 1 APCDD 147495 (APCDD1) Homo sapiens GRAM domain GRAMD4 23151 containing 4 (GRAMD4) Homo sapiens late cornified LCE1A 3531 31 envelope 1A (LCE1A) Homo sapiens CXXC finger 5 51523 (CXXC5) Homo sapiens sprouty homolog 2 SPRY2 10253 DrOSOOhila) (SPRY2

FZD2 O.96O 2.7E-35 2535 DroSophila) (FZD2 e kappaHomo sapienslight polypeptide nuclear factor gene of NFKBIA 0.963 8.5E-14 4792 enhancer in B-Cells inhibitor ITGA2 Homo sapiens integrin Homo sapiens family with FAM13A sequence similarity 13 Homo sapiens V-maf musculoaponeurotic fibrosarcoma MAFB oncogene homolog B Homo sapiens cartilage oligomeric COMP matrix Orotein (COMP exar Homo sapiens coxsackie virus and CXADR 1.O14 2.5E-10 1525 adenovirus receptor (CXADR Homo sapiens pre-B-cell leukemia PBX3 homeobox 3 (PBX3) Homo sapiens chemokine (C-X-C CXCL2 motif) ligand 2 (CXCL2) Homo sapiens chemokine (C-C CCL2 motif) ligand 2 (CCL2) SEMA6A Homo Sapiens Sema domain Homo sapiens LFNGO fucosylpeptide 3-beta-N- LFNG 1.057 2.9E-12 3955 acetylglucosaminyltransferase Homo sapiens matrix Gla protein MGP 1.064 1.OE-09 4256 (MGP) Homo sapiens aldehyde dehydrogenase 2 family ALDH2 1.113 2.7E-35 217 (mitochondrial) (ALDH2) Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 23 of 60 US 2015/0217131 A1

Log 2 fold Entrez Gene symbol change p-value gene ID Definition Homo sapiens microRNA 1978 MR1978 1.116 2.7E-35 100302173 (MIR1978) Homo sapiens inhibitor of DNA D 1.121 5.OE-18 3397 binding 1 Homo sapiens matrix metallopeptidase 11 (stromelysin 3) MMP 11 1.129 1.OE-12 4320 MMP 11

ZNF395 1.155 27Essl2.7E-35 55893sess 395Homo (ZNF395 sapiens zinc finger protein Homo sapiens cell division cycle 25 CDC25B 1184 homolog B (S. pombe) (CDC25B) Homo sapiens plasminogen PLAU 1.190 activator MSMB 1.211 Homo sapiens microseminoprotein Homo sapiens serum/glucocorticoid regulated SGK 1.250 kinase (SGK) Homo sapiens inhibitor of DNA D3 1271 binding 3 Homo sapiens chemokine (C-X-C CXCL1 1.313 motif) licland 1 ZMZ 1.322 571.78 Homo sapiens zinc finger Homo sapiens serine/threonine MGC42105 1.33 167359 protein kinase NIM1 (MGC42105) Homo sapiens inhibitor of DNA D2 1.358 3398 binding 2 Homo sapiens solute carrier family SLC2A1 1.375 6513 2 (facilitated aluCOSe transporter Homo sapiens serum/glucocorticoid regulated SGK1 1384 2.7E-35 6446 kinase 1 (SGK1) Homo sapiens cyclin-dependent CDKN1C 1479 2.7E-35 1028 kinase inhibitor 1C (p57 ENO2 1.671 2.7E-35 2026 Homo sapiens enolase 2 (gamma Homo sapiens N-myc downstream NDRG1 1.691 2.7E-35 10397 regulated gene 1 (NDRG1) RASL11B 1.769 2.7E-35 65997 Homo sapiens RAS-like Homo sapiens late cornified LCE5A 2.030 2.7E-35 254910 envelope 5A (LCE5A) Homo sapiens 6-phosphofructo-2- PFKFB4 2.492 2.7E-35 521 O kinase/fructose-2 Figure 4 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 24 of 60 US 2015/0217131 A1

Log 2 Gene fold Errez symbol change p-value gene ID | Definition PREDICTED: Homo sapiens similar to LOC728454 -4.17 24E-O6 728454 Beta-defensin 2 precursor DEFE4 -3.909 1.3E-30 1673 Homo sapiens defensin DEFEO3A -2.684 4.OE-06 55894 Homo Sapiens defensin LCN2 -2.179 1.9E-08 3934 Homo sapiens lipocalin 2 (LCN2) Homo sapiens late cornified envelope LCE3D -2.091 9.5E-08 84648 3D (LCE3D) Homo sapiens late cornified envelope LCE3E - 1987 1.4E-11 3531453E (LCE3E) Homo sapiens small proline-rich SPRR2A - 1953 1.1 E-27 6700 protein 2A (SPRR2A) Homo sapiens S100 calcium binding S100A7A -1.777 2.3E-31 338324 protein A7A (S100A7A) Homo sapiens small proline-rich SPRR3 -1.767 1.3E-30 6707 protein 3 (SPRR3) Homo sapiens small proline-rich SPRR2B -1.765 8.6E-23 6701 protein 2B (SPRR2B) Homo sapiens tribbles homolog 3 TRIB3 - 1745 5.9E-10 57761 (Drosophila) (TRIB3) Homo sapiens matrix metallopeptidase MMP3 - 1687 2.7E-03 4314 || 3 (stromelysin 1 KRT34 - 1.650 1.1E-08 3885 Homo Sapiens Keratin 34 (KRT34 Homo sapiens S100 calcium binding S100A12 - 1608 4.5E-07 6283 protein A12 (S100A12) Homo sapiens dehydrogenase/reductase (SDR DHRS9 - 1608 1.4E-03 10170 family) member 9 (DHRS9) Homo sapiens galectin-related protein HSPC159 - 1596 8.6E-23 29094 (HSPC159) IL1A - 1573 1.OE-09 3552| Homo sapiens interleukin 1 ATP12A - 1567 8.6E-28 479 Homo sapiens ATPase Homo sapiens secretory leukocyte SLP - 1562 4.6E-2O 6590 peptidase inhibitor (SLP) Homo sapiens small proline-rich SPRR2C - 1550 1.3E-3O 6702 protein 2C (pseudogene) (SPRR2C) PLA2G4D - 1525 3.2E-15 283748 Homo sapiens phospholipase A2 Homo sapiens cysteine-rich C-terminal NICE-1 -1488 3.1E-06 54544 1 (CRCT1) Homo sapiens DNA-damage-inducible DDT4 - 1.428 7.6E-12 54541 transCriot 4 (DDT4 Homo sapiens WAP four-disulfide core WFDC12 - 1.388 2.4E-02 128488 | domain 12 (WFDC12) ACQP9 - 1.375 6.9E-1 366 | Homo sapiens acquaporin 9 (AOP9) Figure 5 Patent Application Publication Aug. 6, 2015 Sheet 25 of 60 US 2015/0217131 A1

Log 2 Gene fold Erez symbol change p-value gene ID | Definition Homo Sapiens Serpin peptidase SERPINB4 - 1365 2.1 E-18 6318 inhibitor Homo sapiens corneodesmosin CDSN - 1.363 4.9E-08 1041 (CDSN) KIAA 199 - 1.357 7.7E-08 57214 | Homo sapiens KIAA1199 (KIAA1199) Homo sapiens small proline-rich SPRR2D - 1.352 2.5E-25 6703 protein 2D (SPRR2D) CNFN -1.346 1.9E-06 84518 Homo sapiens cornifelin (CNFN) Homo sapiens carboxypeptidase A4 CPA4 - 1.333 5.7E-O7 51200 (CPA4) Homo sapiens late cornified envelope LCE3A - 1.32O 9.8E-03 3531423A (LCE3A WL - 1318 15E-18 3713 Homo sapiens involucrin (IVL) RNASE7 - 1.313 S.OE-O7 84659 Homo Sapiens ribonuclease Homo sapiens ArfGAP with dual PH ADAP2 - 1307 54E-O7 558O3 domains 2 (ADAP2 Homo sapiens partner of NOB1 PNO1 - 1.304 4.9E-2O 56902 homolog (S. cerevisiae) (PNO1) PREDICTED: Homo sapiens cystatin CST6 - 1:303 16E-O3 1474 E/M (CST6) DEFE1 - 1.283 3.1E-25 1672 Homo Sapiens defensin Homo sapiens apolipoprotein B APOB - 1271 3.9E-03 338 (including Ag(x) antigen) (APOB) CTSL2 - 1.267 8.OE-15 1515 Homo sapiens cathepsin L2 (CTSL2 KRT80 - 1.263 2.4E-08 144501 | Homo sapiens keratin 80 (KRT80) Homo sapiens open C1 Orf68 - 1.245 4.2E-O3 1E-08 |reading frame 68 (C1orf68) KRT78 - 1.238 9.OE-04 196374 Homo sapiens keratin 78 (KRT78) HER PUD1 - 1.237 6.2E-O7 9709 Homo sapiens homocysteine-inducible Homo sapiens LY6/PLAUR domain LYPD5 -1.223 5.6E-09 284348 Containing 5 (LYPD5 HPSE - 1223 5.1E-O5 10855 Homo sapiens heparanase (HPSE) Homo sapiens solute carrier family 5 SLC5A1 - 1.221 3.3E-O7 6523 (sodium/glucose cotransporter) Homo sapiens S100 calcium binding SOOP -1.218 9.4E-05 6286 protein P (S100P) Homo sapiens spinster homolog 2 SPNS2 - 1215 1.OE-12 124976 (Drosophila) (SPNS2) ZFP36 - 1.98 4.1E-05 7538 Homo sapiens zinc finger protein 36 L1F10 - 1.195 7.2E-O4 84639 Homo sapiens interleukin 1 family Homo sapiens serpin peptidase SERPINB7 - 1,195 4.6E-16 8710 inhibitor Homo sapiens chromosome 9 open C9Orf169 - 1.188 9.8E-O6 375791 reading frame 169 (C9orf169) ARG1 - 117O 4.8E-O6 383 Homo sapiens arginase Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 26 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez SWinbol Chande p-value cene ID | Definition Homo sapiens serpin peptidase SERPINB3 - 1153 54E-09 6317 inhibitor Homo sapiens lymphocyte antigen 6 LY6G6C - 1.151 2.7E-O4 80740 COmolex Homo sapiens kallikrein-related KLK5 -1. 145 5.9E-05 25818 peptidase 5 (KLK5) Homo sapiens SH2B adaptor protein 3 SH2B3 - 1.143 3.6E-O7 10019 (SH2B3) Homo sapiens nuclear import 7 NP7 - 1.134 7.6E-O7 51388 homolog (S. cerevisiae) (NIP7) Homo sapiens serpin peptidase SERPINB13 - 1130 1.2E-05 5275 inhibitor Homo sapiens hypothetical protein HSPC111 - 1.121 5.9E-14 51491 HSPC111 (HSPC111) Homo sapiens glutathione S GSTT2 - 102 2.6E-05 653689 transferase theta 2 (GSTT2 Homo sapiens nucleoside NP -1. O1 1.3E-O4 4860 phosphorylase (NP) Homo sapiens GTP binding protein 4 GTPBP4. - 1.101 2.4E-06 23560 (GTPBP4) Homo sapiens polymerase (RNA) || (DNA directed) polypeptide B POLR3B -1099 2.3E-12 557O3 (POLR3B NT5C3 - 1088 9.5E-04 51251 Homo sapiens 5'-nucleotidase Homo sapiens interferon-induced FT1 - 1085 1.7E-08 3434 protein with tetratricopeptide repeats 1 Homo sapiens serine peptidase SPINK5 -1081 2.5E-05 11 OO5 inhibitor Homo sapiens dyskeratosis congenita DKC1 -1.O72 7.8E-06 1736 Homo sapiens dual specificity DUSP - 1071 6.9E-04 1843 phosphatase 1 (DUSP1) Homo sapiens dual specificity DUSP14 - 1069 7.4E-09 11072 phosphatase 14 (DUSP14) L13RA2 - 1.066 4.4E-02 3598 Homo Sapiens interleukin 13 receptor Homo sapiens insulin-degrading IDE - 1.064 3.8E-08 3416 enzyme (IDE) PRSS27 - 1.064 2.7E-03 83886 Homo sapiens protease Homo sapiens immediate early IER3 - 1059 4.1E-05 8870 response 3 (IER3) PLA2C4B - 1.058 6.4E-03 8681 Homo sapiens phospholipase A2 Homo sapiens Ly1 antibody reactive LYAR - 1.057 6.7E-04 55646 homolog (mouse) (LYAR) Homo sapiens solute carrier family 30 SLC30A1 - 1055 2.8E-09 7779 (zinc transporter)

Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 27 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez symbol change p-value gene ID | Definition Homo sapiens elongation of very long ELOVL4 - 1054 2.OE-04 6785 chain fatty acids (FEN1/Elo2 Homo sapiens caspase recruitment CARD18 - 1.050 1.3E-08 59082 domain family SFRS6 - 1.049 4.1E-12 6431 || Homo sapiens splicing factor Homo sapiens chromosome 17 open C7orfg1 - 1041 11E-O7 84981 reading frame 91 (C17orf91) Homo sapiens NOP16 nucleolar NOP16 - 1035 3.6E-08 51491 Orotein homolod (yeast) (NOP16 ABCE1 - 1.032 14E-O7 6059 Homo sapiens ATP-binding cassette Homo sapiens nuclear factor NFE2L3 - 1.031 11 E-05 9603 (erythroid-derived 2)-like 3 (NFE2L3) STC1 - 1031 14E-O7 6781 Homo sapiens stanniocalcin 1 (STC1) Homo sapiens thioredoxin interacting TXNP - 1.02O 2.5E-03 10628 protein (TXNP) Homo sapiens MAK16 homolog (S. MAK16 -O2O 5.OE-05 84549 cerevisiae) (MAK16) Homo sapiens transglutaminase 3 (E TGM3 -1.O12 7.3E-04 7053 polypeptide Homo sapiens arachidonate ALOXE3 - 1.010 1.7E-O4 59344 lipoxvdenase 3 (ALOXE3 Homo sapiens NOP58 ribonucleoprotein homolog (yeast) NOP58 - 1010 9.8E-O6 51602 (NOP58) KIAAOO2O -1.O1 O 1.3E-09 9933 Homo sapiens KIAA0020 (KIAA0020) Homo sapiens arginine vasopressin AVP1 -O.991 1.4E-04 60370 induced 1 (AVP1) Homo sapiens family with sequence FAM43A -O.991 58E-08 131583 similarity 43 Homo sapiens non-specific cytotoxic NCCRP1 -O.990 2.4E-O7 342897 cell receptor protein 1 homolog TUBB3 -0.982 5.OE-02 10381 Homo Sapiens tubulin Homo sapiens MAP7 domain MAP7D1 -0.971 1.7E-O2 55700 containing 1 (MAP7D1) Homo sapiens low density lipoprotein receptor (familial LDLR -O.969 8.9E-04 3949 hypercholesterolemia) TUBB4C) -O.965 3.9E-10 56604 || Homo Sapiens tubulin Homo sapiens sphingomyelin SMPD3 -0.957 1.1E-O4 55512 phosphodiesterase 3 Homo sapiens chromosome 6 open C6Orf66 -0.957 7.7E-08 29078 reading frame 66 (C6orf66) CYP4F22 -O.953 11E-03 12641 O Homo Sapiens Cytochrome P450 Homo Sapiens Sialic acid SIAE -O.953 3.2E-O2 54414 acetylesterase (SAE) Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 28 of 60 US 2015/0217131 A1

Log 2 Gene fold Errez SVnbol Chance O-Value Gene ID | Definition else nucleotideHomo sapiens exchange rhofrac factor guanine (GEF) 2 ARHGEF2 -O. 949 3.9E-06 9181 (ARHGEF2 oes sea Homo sapiens karyopherin alpha 4 KPNA4 -O.945 4.6E-O3 3840 importin alona 3) KPNA4 TUBA4A 7277 | Homo sapiens tubulin Homo sapiens DEAD (Asp-Glu-Ala DDX21 9188 Asp) box polypeptide 21 (DDX21) Homo sapiens small proline-rich SPRR2F 6705 protein 2F (SPRR2F) Homo sapiens threonyl-tRNA TARS 6897 Swnthetase (TARS TUFT1 7286 Homo Sapiens tuftelin 1 (TUFT1 PSMD12 -O.934 2.1E-O7 5718 Homo sapiens proteasome (prosome ASPRV -O.923 7.5E-06 151516 || Homo Sapiens aspartic peptidase

CARS -O.922ospel 36E-04assos 833 SynthetaseHomo sapiens (CARS cysteinyl-tRNA

HSPB8 -O.917or 4.2E-05eos 26353 HomoOrotein sapiens 8 (HSPB8 heat shock 22kDa TFRC 7037 | Homo sapiens transferrin receptor (p90 Homo sapiens serine peptidase SPINK6 4042O3 inhibitor Homo sapiens myxovirus (influenza MX1 4599 virus) resistance 1 Homo sapiens nucleolar protein 11 NOL11 25926 (NOL11) Homo sapiens chromosome 1 open COrf 16 79098 readino frame 116 (C1 orf1 16 Homo sapiens glutathione S transferase theta 2B GSTT2B -O.895 3.9E-O 653689 (Cene/OSeudodene

MSX -O.895oes also2.1E-04 4487 Homo(MSX1 sapiens msh homeobox 1 oes its Homo sapiens Kruppel-like factor 9 KLF9 -O.894 1.4E-O5 687 (KLF9 one methylglutaryl-CoenzymeHomo sapiens 3-hydroxy-3- A reductase HMGCR -0893 9.OE-09 3156 (HMGCR oegal asso, Homo sapiens exosome component 6 EXOSC6 -O.893 3.5E-O7 18460 (EXOSC6

BCLAF -O.891oe, 9.8E-O4so 9774 transcriptionHomo sapiens factor BCL2-associated 1 (BCLAF1 SLC 11A2 -O.891 1.2E-O7 4891 Homo sapiens solute carrier family 11 Homo sapiens deoxyribonuclease I-like DNASE1L2 -O.885 8.OE-07 17752 (DNASE1L2) Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 29 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez symbol change p-value gene ID | Definition Homo sapiens AP2 associated kinase AAK1 -0.885 1.7E-09 22848 1 (AAK1) Homo sapiens chromodomain helicase CHD1 -0.884 2.8E-03 1105 DNA binding protein 1 (CHD1) Homo sapiens DEAD (Asp-Glu-Ala DDX5 -O.883 1.1E-03 1655 Asp) box polypeptide 5 (DDX5) Homo sapiens NOP2/Sun domain NSUN2 -O.882 1.2E-O2 54888 fami Homo sapiens ring finger protein 103 RNF103 -0.877 4.2E-O7 (RNF103) Homo sapiens dual specificity DUSP5 -O.873 6.6E-05 1847 phosphatase 5 (DUSP5) Homo sapiens ribonuclease P/MRP RPP40 -0.872 6.7E-04 10799 40kDa subunit (RPP40) Homo sapiens gamma-glutamyl GGCT -O.869 2.7E-04 79017 CVClotransferase (GGCT Homo sapiens family with sequence FAM62C -O.861 4.3E-02 83850 similarity 62 (C2 domain containing) MUCL1 -O.857 2.4E-02 118430 Homo sapiens mucin-like 1 (MUCL1) Homo sapiens glycyl-tRNA synthetase GARS -O.856 2.7E-04 Homo sapiens zinc finger protein 207 ZNF2O7 -0.855 2.2E-02 7756 (ZNF207) Homo sapiens protein arginine PRMT3 -O.855 1.2E-05 101.96 methyltransferase 3 (PRMT3 Homo sapiens exosome component 9 EXOSC9 -0.854 4.8E-03 5393 (EXOSC9) Homo sapiens protein phosphatase 2 PPP2CA -O.854 4.4E-05 5515 (formerly 2A proliferation-associated 1 like 2 SPA L2 -O.854 2.7E-04 57568 Entre.(SIPAL2 Homo sapiens intermediate filament FFO2 -O.852 5.5E-03 family orphan 2 (IFFO2) Homo sapiens AKT interacting protein AKTIP -O.85 8.1E-06 644OO (AKTIP Homo sapiens RNA binding motif RBM12 -O.85O 7.5E-05 10137 protein 12 (RBM12)

Homo sapiens ankyrin repeat domain ANKRD57 -O.850 1.9E-05 6512457 (ANKRD57 Homo sapiens PAK1 interacting protein PAK1P1 -O.85O 6.2E-05 55003 || 1 (PAK1P1) Homo sapiens DIM1 dimethyladenosine transferase 1-like DMT1L. -0.848 4.OE-04 27292 (S. cerevisiae) CRNN -O.846 1.7E-O2 49860 Homo sapiens cornulin (CRNN) Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 30 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez symbol change p-value gene ID | Definition Homo sapiens chloride intracellular CLIC3 -O.845 7.5E-10 9022 channel 3 (CLIC3) Homo sapiens WAP four-disulfide core WFDC5 -O.843 56E-04 149708 domain 5 (WFDC5) Homo sapiens hydroxyprostaglandin

HPGD -O.836 3.8E-04 3248 dehydrodenase 15-(NAD) (HPGD Homo sapiens LTV1 homolog (S. LTV 84946 cerevisiae) (LTV1) Homo sapiens feline leukemia virus FLVCR2 55640 subgroup C cellular receptor family CD24 1E--08 || Homo sapiens CD24 molecule (CD24) Homo sapiens phosphomannomutase PMM2 53732 (PMM2) Homo sapiens keratinocyte proline-rich KPRP 448834 protein (KPRP) PRSS3 5646 Homo sapiens protease ANXA3 306 Homo Sapiens annexin A3 (ANXA3 UTP 1.1L -O.823 1.1E-03 51118 Homo sapiens UTP11-like Homo sapiens small proline-rich SPRR2E -O.822 1.1E-1O 6704 Orotein 2E (SPRR2E Homo sapiens chromosome 1 open

C1 Orf63 -O.822 1.2E-03 57035 reading frame 63 (C1 Orf63 Homo sapiens INO80 complex subunit NO8OC 125476 C (NO80C) Homo sapiens filaggrin family member FLG2 3886982 (FLG2) Homo sapiens CDV3 homolog (mouse) CDV3 55573 (CDV3) Homo sapiens chromatin modifying CHMP4C 92421 protein 4C (CHMP4C) Homo sapiens solute carrier family 15 SLC 15A1 6564 (oligopeptide transporter) Homo sapiens ELMO/CED-12 domain ELMOD1 55531 containing 1 (ELMOD1) ATP6V1 C2 245973 Homo sapiens ATPase Homo sapiens calmodulin regulated CAMSAP1L1 23271 Spectrin-aSSOciated Orotein 1-like 1 Homo sapiens DNA-damage-inducible DDT3 -O.802 2.5E-04 1649 transcript 3 (DDT3 Homo sapiens receptor-interacting RIPK2 -O.8OO 2.6E-O6 8767 Serine-threonine kinase 2 (RPK2 Homo sapiens IGF-like family member GFL2 -O.8OO 3.5E-O7 14792O 2 GFL2 DNAUB9 -0.797 2.5E-04 4189Homo sapiens DnaJ (Hsp40) homolog Homo sapiens heme oxygenase HMOX1 -O.796 3.OE-07 3162 (decycling) 1 (HMOX1) Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 31 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez SWnbol Chance O-Value dene ID | Definition Homo sapiens salt-inducible kinase 1 SK1 -O.794 4.9E-03 15OO94 (SK1 Homo sapiens PYD (pyrin domain) PYDC1 -O.790 18E-10 260434 Containind 1 (PYDC1 Homo sapiens ring finger protein 39 RNF39 -O.789 18E-O6 8O352 (RNF39 CRYAB -0.784 4.OE-O2 1410 | Homo sapiens crystallin Homo sapiens CDC-like kinase 1 CLK1 -0.781 3.1E-03 1195 (CLK1 Homo sapiens hypothetical protein FLU22662 -0.777 4.9E-O2 79887 FLJ22662 (FLJ22662) Homo sapiens transmembrane protein TMEM79 -0.776 2.1E-O2 84.283 79 (TMEM79 Homo sapiens family with sequence FAM107B -0.775 4.1E-O5 83641 similarity 107 Homo sapiens tumor necrosis factor TNFRSF12A -0.774 3.5E-02 51330 receptor superfamily Homo sapiens seven in absentia SAH2 -0.774 14E-05 6478 homolog 2 (Drosophila) (SIAH2) Homo sapiens ubiquitin-like domain containing CTD phosphatase 1 UBLCP1 -0.772 5.6E-12 134510 (UBLCP1) Homo sapiens small proline-rich SPRR2G -0.772 8.3E-11 6706 protein 2G (SPRR2G) L1F9 -O.77O 3.9E-06 56300 | Homo Sapiens interleukin 1 famil Homo sapiens open C8Orf13 -0.77O 6.1E-O6 83648 readind frame 13 (C8Orf13 KIAAO247 -O.769 1.8E-O2 9766 HOmo Saoiens KIAAO247 (KIAAO247 Homo sapiens chromatin modifying CHMP1B -O.767 3.2E-O2 57132 protein 1B (CHMP1B) Homo sapiens centromere protein T CENPT -0.762 3.1E-O2 8O152 (CENPT Homo sapiens WW and C2 domain WWC 1 -O.761 2.2E-O2 23286 Containind 1 (WWC1 Homo sapiens transmembrane emp24 TMED5 -0.757 3.2E-03 50999 protein transport domain containing 5 Homo sapiens SCO cytochrome oxidase deficient homolog 1 (yeast) SCO1 -O.752 2.2E-02 6341 (SCO1 Homo sapiens thioredoxin domain TXNDC9 -O.752 1.3E-O2 101.90 containing 9 (TXNDC9) Homo sapiens interferon stimulated SG20 -O.751 2.4E-O6 3669 exonuclease dene 20kDa (ISG20 Homo sapiens cellular repressor of CREG1 -0.750 2.7E-O2 8804 E1A-stimulated genes 1 (CREG1) Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 32 of 60 US 2015/0217131 A1

Log 2 Gene fod Entrez SVnbol Chance O-Value Gene ID | Definition Homo sapiens chromosome 12 open C12Orf5 -O.749 5.5E-03 57.103 reading frame 5 (C12orf5) Homo sapiens family with sequence FAM25G -0.747 3.OE-03 1E--08 similarity 25 HIST2H2BE -O.746 2.5E-06 8349 Homo sapiens histone cluster 2 Homo sapiens guanine nucleotide binding protein-like 3 (nucleolar) GNL3 -O.746 3.5E-02 26354 Homo sapiens kallikrein-related KLK8 -O.742 5.5E-05 11202 peptidase 8 (KLK8) Homo sapiens WD repeats and SOF1 WDSOF1 -O.742 1.2E-08 25879 domain containing (WDSOF1) Homo sapiens sterile alpha motif SAMD9 -O.74O 1.5E-02 54809 domain containing 9 (SAMD9) Homo sapiens solute carrier family 20 SLC20A1 -O.74O 4.4E-O2 6574 (phosphate transporter) Homo sapiens teashirt zinc finger TSHZ3 -O.735 7.9E-07 57616 Homo sapiens 3-hydroxy-3- HMGCS1 -0.735 7.6E-O4 3157 methylglutary-Coenzyme A synthase 1 Homo sapiens chromosome 6 open C6orf153 -O.733 2.1E-O3 88745 reading frame 153 (C6orf 153) Homo sapiens solute carrier family 30 SLC30A7 -O.73O 3.OE-03 148867 (zinc transporter) Homo sapiens family with sequence FAM167A -O.73O 3.7E-O3 83648 similarity 167 ZFAND2A -O.729 3.1E-06 90637 Homo Sapiens zinc finder Homo sapiens nexilin (Factin binding NEXN -O.727 2.3E-O3 91624 Orotein). NEXN ZFP36L1 -O.725 2.OE-02 677 Homo sapiens zinc finger protein 36 Homo sapiens metallothionein 1G MT1G -O.723 16E-06 4495 (MT1G XKRX -O.723 8.3E-O3 4024.15 Homo sapiens NOP56 ribonucleoprotein homolog (yeast) NOP56 -0.722 1.1E-03 10528 (NOP56) Homo sapiens transmembrane 4 L six TM4SF1 -O.716 1.OE-03 4071 family member 1 (TM4SF1) SCNN1B -0.716 1.1E-03 6338. Homo sapiens sodium channel Homo sapiens tetratricopeptide repeat TTC27 -O.714 2.1E-O4 55622 domain 27 (TTC27) Homo sapiens small proline-rich SPRR1B -0.713 4.E-05 6699 Orotein B (COrnifin) (SPRR1B Homo sapiens mRNA turnover 4 MRTO4 -0.712 3.5E-02 51154 homolog (S. cerevisiae) (MRTO4) Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 33 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez S Winbol Chance O-Value Gene ID | Definition Homo sapiens ribosomal protein S7 RPS7 -0.7 21E-O6 6201 (RPS7) SYNCRP -O.71O 1.2E-O2 10492 | Homo Sapiens SVnaototaOmin bindino Homo sapiens RNA binding motif RBM25 -0.709 2.4E-03 58517 | protein 25 (RBM25) PPL -O.7O6 4.7E-O3 54.93| Homo sapiens periplakin (PPL) Homo sapiens eukaryotic translation EIF2S -O.7O6 3.OE-06 1965 initiation factor 2 Homo sapiens kinesin family member KF13B -O.7O6 4.4E-O2 23303 13B (KIF13B) Homo sapiens serpin peptidase SERPINA3 -O.705 1.9E-04 12 inhibitor Homo sapiens carbohydrate (N- acetylglucosamine 6-O) CHST7 -0.705 2.7E-05 56548 Sulfotransferase 7 GRPEL1 -O.705 4.2E-O2 80273 Homo sapiens GrpE-like 1 XPO4 -0.705 1.OE-04 64328 Homo sapiens exportin 4 (XPO4) Homo sapiens histidine ammonia-lyase HAL -0.703 8.OE-03 3034 (HAL) Homo sapiens polymerase (RNA) POLR1C -O.701 2.3E-04 9533 polvoeotide C CD55 -O.7OO 18E-O2 1604 || Homo sapiens CD55 molecule Homo sapiens kelch-like 18 KLHL18 -O.699 2.6E-O3 23276 (Drosophila) (KLHL18) Homo sapiens K(lysine) KAT2B -0.699 1.3E-O2 885O acetyltransferase 2B (KAT2B COO3 -O.697 6.1E-06 51805 || Homo sapiens coenzyme Q3 homolog DNAJC9 -0.695 4.9E-02 23234 Homo Sapiens DnaJ (Hsp40) homoloo Homo sapiens tRNA splicing endonuclease 15 homolog (S. TSEN15 -O.695 18E-O3 116461 cerevisiae) TSPYL -0.692 2.4E-04 7259 Homo Saoiens TSPY-like 1 (TSPYL Homo sapiens coenzyme Q10 COO 10B -0.691 4.3E-O2 80219 homolog B (S. cerevisiae) (COG10B) Homo sapiens DEAD (Asp-Glu-Ala DDX10 -O.691 2.7E-04 1662 Asp) box polypeptide 10 (DDX10) HIST1HC -0.690 2.1E-O2 3006 || Homo sapiens histone cluster 1 Homo sapiensatlastin GTPase 3 ATL3 -0.687 2.OE-03 25923 (ATL3) Homo sapiens ribosomal RNA RRP 15 -0.684 9.8E-03 51018 processino 15 homolod (S. cerevisiae Homo sapiens churchill domain CHURC1 -O.683 1.9E-O2 91612 containing 1 (CHURC1) Homo sapiens solute carrier family 7 SLC7A1 -O.683 1.1E-O2 6541 (cationic amino acid transporter Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 34 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez symbol change p-value gene ID | Definition Homo sapiens topoisomerase (DNA) TOP 1P2 -O.681 1.1E-04 7152 pseudogene 2 (TOP1P2) Homo sapiens transmembrane 7 TM7SF2 -O,681 2.OE-02 7108 superfamily member 2 (TM7SF2) Homo sapiens coiled-coil domain CCDC86 -0.68O 3.2E-03 79080 containing 86 (CCDC86) Homo sapiens basic helix-loop-helix BHLHB2 -0.68O 21E-03 8553 domain Containino P3 -O,679 1.9E-10 Homo sapiens peptidase inhibitor 3 Homo sapiens CAP-GLY domain CLIP1 -0.677 4.8E-O2 containing linker protein 1 (CLIP1) Homo sapiens E2F transcription factor E2F3 -O.676 1.3E-02 3 (E2F3) HIST2H2AA3 -0.676 4.9E-08 Homo sapiens histone cluster 2 SCNN1A -0.676 1.4E-O2 Homo Sapiens Sodium Channel essel Homo sapiens open C20OrfA. -0.673 1.3E-03 25980 reading frame 4 (C20orf4 Homo sapiens sperm associated SPAG1 -O.673 5.OE-03 6674 antigen 1 (SPAG1) TFB2M -0.673 2.OE-04 64216 Homo sapiens transcription factor B2 Homo sapiens absent in melanoma 1 AM1 -0.671 3.9E-05 202 (AIM1) Homo sapiens BCL2/adenovirus E1B BNPL -0.671 3.4E-02 149428 19kD interactino Orotein like (BNPL age Homo sapiens heat shock 70kDa HSPA4 -0.67O 7.OE-03 33O8 Orotein 4 (HSPA4 acces Homo sapiens SRR1 domain SRRD -0.666 1.9E-06 402O55 COntaining (SRRD Homo sapiens transforming growth TGFA -0.666 2.3E-O2 7039 factor Homo sapiens spire homolog 1 SPIRE1 -O.665 1.OE-O2 56907 | (Drosophila) (SPIRE1) SPRED1 -O.665 3.7E-02 161742 Homo sapiens sprouty-related Homo sapiens family with sequence FAM84B -O,664 1.6E-02 157638 similarity 84 Homo sapiens ankyrin repeat domain ANKRD22 -0.663 1.6E-02 118932 22 (ANKRD22) Homo sapiens UbiA prenyltransferase UBIAD -0.663 3.2E-02 29914 domain Containino. 1 (UBIAD1 Homo sapiens MAX dimerization MXD1 -0.658 18E-02 4084 protein 1 (MXD1) Homo sapiens mitochondrial ribosomal MRPS10 -0.658 3.7E-O2 55173 protein S10 (MRPS10) Homo sapiens interferon regulatory RF9 -O,656 4.1E-03 10379 factor 9 (IRF9) GFM1 -0.656 3.4E-02 85476 Homo sapiens G elongation factor Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 35 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez SVimbol Chande O-Value cene ID | Definition races PREDICTED: Homo sapiens similar to LOC73O833 -0.654 3.2E-04 73O833 filacCrin (LOC73O833 toe, Homo sapiens cyclin-dependent kinase CDKN1B -O.654 4.8E-03 1027 inhibitOr 1B (p27 Homo sapiens syndecan binding SDCBP2 -0.654 3.OE-03 271 11 protein (syntenin) 2 (SDCBP2) Homo sapiens eukaryotic translation EIF6 -0.653 3.5E-05 3692 initiation factor 6 (EIF6) GRPEL2 -0.652 7.9E-04 134266 Homo sapiens GrpE-like 2 Homo sapiens CCAAT/enhancer CEBPG -0.651 1.2E-06 1054 binding protein (C/EBP) Homo Sapiens asparagine Synthetase ASNS -O.650 1.5E-02 440 (ASNS Homo Sapiens asparagine-linked glycosylation 13 homolog (S. ALG13 -O.650 5.6E-03 55849 cerevisiae) Homo sapiens GAR1 ribonucleoprotein GAR1 -0.649 7.OE-03 54433 homolog (yeast) (GAR1) Homo sapiens eukaryotic translation EIF4E2 -0.649 6.9E-04 9470 initiation factor 4E family member 2 Homo sapiens integrin beta 4 binding ITGB4BP -O.649 1.8E-04 3692 protein (ITGB4BP) Homo sapiens ribonuclease H1 RNASEH1 -O.648 3.3E-O2 246243 (RNASEH1) Homo sapiens ClpX caseinolytic CLPX -0.648 9.7E-03 10845 peptidase X homolog (E. coli) (CLPX) Homo sapiens WD repeat domain 12 WDR12 -0.647 1.9E-02 55759 (WDR12) Homo sapiens solute carrier family 1 SLCA5 -0.646 2.E-03 6510 (neutral amino acid transporter) Homo sapiens basic transcription BTF3L4 -0.646 8.4E-03 9.408 factor 3-like 4 (BTF3L4 Homo sapiens AXN1 up-regulated 1 AXUD1 -0.644 3.7E-03 (AXUD1) Homo sapiens ubiquitin carboxyl terminal esterase L3 (ubiquitin UCHL3 -0.641 1.9E-04 thiolesterase) Homo sapiens patatin-like phospholipase domain containing 8 PNPLA8 -0.640 2.9E-02 PNPLA8 a Homo sapiens methionyl-tRNA MARS -0.639 4.6E-06 4141 Synthetase (MARS PPP1R15A -0.638 2.8E-04 Homo Sapiens Orotein phOSOhatase 1 is, Homo sapiens syntaxin binding protein STXBP5 -O.636 5.8E-04 134957 5 (tOmoSVn) (STXBP5

Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 36 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez

SVnbol Chance o-Wallie Gene ID | Definition

PISD loss-0.635 2Es2.2E-04 23761 Homodecarboxylase sapiens phosphatidylserine(PISD oes sea Homo sapiens myotubularin related MTMR6 -O.629 8.9E-03 91 Of Orotein 6 MTMR6 oes less Homo sapiens zinc finger protein 593 ZNF593 -O.629 16E-05 51042 (ZNF593

ANKRD33 -O.628oceal 6.9E-04seal 341405 33Homo (ANKRD33 sapiens ankyrin repeat domain NT5C2 Homo sapiens 5'-nucleotidase Homo Sapiens Suppressor of variegation 4-20 homolog 1 SUV42OH1 DrOSOOhila) (SUV42OH1

EIF3J -0.62Oosco escal6.3E-03 8669 initiationHomo Sapiens factor eukaryotic3 translation Homo sapiens fatty acid binding protein 5 (psoriasis-associated) FABP5 2171 (FABP5) Homo sapiens serpin peptidase SERPINB8 5271 inhibitor Homo sapiens ATG2 related 2 homolog A (S. cerevisiae) ATG2A 23130 (ATG2A) Homo sapiens late cornified envelope LCE2D 353141 2D (LCE2D) Homo sapiens cleavage stimulation CSTF2 1478 factor Homo sapiens coiled-coil domain CCDC12 151903 containing 12 (CCDC12) Homo sapiens bromodomain BRD2 6046 containing 2 (BRD2) Homo sapiens dynactin 5 (p23) DCTN5 84516 (DCTN5) SEMA4D 10507 || Homo sapiens sema domain SLC25A44 9673 Homo Sapiens Solute Carrier family 25 oes see Homo Sapiens pregnancy-associated PAPPA -0.605 3.6E-O2 olasma Orotein A BYSL -0.604 4.9E-02 705 || Homo sapiens bystin-like (BYSL) Homo sapiens transmembrane protein TMEM184C -0.6O2 4.4E-02 55751 184C (TMEM184C) Homo sapiens chromosome 8 open C8Orf33 -0.6O1 1.4E-02 65265 reading frame 33 (C8orf33) Homo sapiens tripartite motif TRIM8 -0.6OO 8.9E-O6 81603 containing 8 (TRIM8) Homo sapiens ribosomal protein S6 RPS6KB -0.6OO 58E-05 61.98 kinase

Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 37 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez sWimbol Chande O-Value Gene ID | Definition Homo sapiens coiled-coil domain CCDC102A O.6O7 2.2E-O2 92922 containing 102A (CCDC102A) Homo sapiens dedicator of cytokinesis DOCK10 O.609 14E-03 55619 10 (DOCK10) Homo sapiens transmembrane protein TMEM194 0.611 8.7E-03 23306 194 (TMEM194) Homo sapiens dehydrogenase/reductase (SDR DHRS3 O619 4.4E-O2 9249 family) member 3 (DHRS3 Homo sapiens NYN domain and retroviral integrase containing NYNRIN O623 15E-07 57523 (NYNRIN Homo sapiens Kruppel-like factor 2 KLF2 O.623 3.9E-05 10365 (lung) (KLF2) Homo sapiens RNA binding motif RBM4B 0.630 6.1E-03 83759 Orotein 4B (RBM4B Homo sapiens zinc finger protein 438 ZNF438 0.643 15E-02 220929 (ZNF438) FNAR1 O.651 4.7E-03 3454 || Homo sapiens interferon (alpha KIAAO 182 0.659 9.2E-05 23199 || Homo sapiens KIAA0182 (KIAA0182) Homo sapiens amyloid beta (A4) APBB3 O.664 1.6E-03 10307 Orecursor Orotein-bindinC Homo sapiens amyloid beta (A4) APBA3 0.664 6.3E-04 9546 precursor protein-binding Homo sapiens nth endonuclease ill NTHL1 0.672 2.1E-03 4913 like 1 (E. coli) (NTHL1) Homo sapiens transmembrane and ubiquitin-like domain containing 1 TMUB 0.676 4.OE-06 83590 (TMUB Homo sapiens dehydrogenase/reductase (SDR DHRS13 0.683 5.OE-02 14705 family) member 13 (DHRS13 Homo sapiens tumor necrosis factor TNFRSF6B O.685 2.1E-04 8771 receptor superfamily Homo Sapiens peroxisomal biogenesis PEX6 0.689 1.6E-03 5190 factor 6 (PEX6) Homo sapiens transmembrane protein TMEM187 O.692 18E-02 8269 187 (TMEM187) Homo sapiens family with sequence FAM11 OB 0.697 14E-02 90362 similarity 110 Homo sapiens transmembrane protein TMEM194A O.7O2 4.3E-03 23306 194A (TMEM194A) ELN O.719 1.1E-02 2006 || Homo sapiens elastin (ELN) Homo sapiens V-maf musculoaponeurotic fibrosarcoma MAFB 0.719 3.3E-02 9935 oncogene homolog B Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 38 of 60 US 2015/0217131 A1

Log 2 Gene food Errez SWinbol Chance o-Walue Gene ID | Definition Homo sapiens HCLS1 binding protein HS 1BP3 O.72O 1.3E-03 643423 (HS1BP3) ITGA2 0.731 3.2E-O2 3673 Homo Sapiens intedrin Homo sapiens glutathione peroxidase GPX2 O.732 3.3E-O2 2877 2 (gastrointestinal) (GPX2) Homo sapiens cell division cycle 2-like CDC2L6 O.74O 2.OE-02 23097 6 (CDK8-like) (CDC2L6) Homo sapiens keratin 9 (epidermolytic KRT9 O.741 1.1E-O3 3857 | palmoplantar keratoderma) (KRT9) Homo sapiens nudix (nucleoside diphosphate linked moiety X)-type NUDT18 O.748 3.6E-O6 79873 motif 18 Homo sapiens AU RNA binding protein/enoyl-Coenzyme A hydratase AUH O.750 4.6E-O3 549 (AUH Homo sapiens solute carrier family 40 SLC4OA1 O.757 4.6E-O2 30061 (iron-regulated transporter) Homo sapiens odd-skipped related 1 OSR1 0.758 6.2E-05 130497 | (Drosophila) (OSR1) Homo sapiens LFNG O-fucosylpeptide 3-beta-N- LFNG 0.771 18E-O2 3955 acetylalucosaminyltransferase Homo sapiens pre-B-cell leukemia PBX3 O.773 4.2E-O2 5090 homeobox 3 (PBX3 ACYP1 0.776 18E-O2 97 Homo sapiens acylphosphatase 1 Homo sapiens GRAM domain GRAMD4 0.779 4.2E-04 23151 containing 4 (GRAMD4) Homo sapiens deltex homolog 2 DTX2 O.78O 4.6E-O5 113878 DroSOOhila) DTX2 SEMA6A O.78O 3.7E-O3 57.556 || Homo sapiens sema domain Homo sapiens prostaglandin F PTGFR 0.795 9.8E-O4 5737 receptor (FP) (PTGFR) Homo sapiens placental growth factor PGF O.807 1.6E-05 5228 (PGF Homo sapiens achaete-scute complex ASCL2 O819 2.5E-03 430 homolog 2 (Drosophila) (ASCL2) Homo sapiens LIM domain binding 2 LDB2 O.82O 3.7E-O2 9079 (LDB2) Homo sapiens G protein-coupled GPRC5C O821 9.4E-04 55890 receptor LAMA5 O822 9.OE-04 3911 || Homo sapiens laminin SLC25A42 O825 5.2E-O3 284439| Homo sapiens solute carrier family 25 Homo sapiens tripartite motif TRIM47 O.830 4.6E-03 91107 containing 47 (TRIM47) Homo sapiens wingless-type MMTV WNT3 O833 18E-O2 7473 integration site family Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 39 of 60 US 2015/0217131 A1

Gene Erez symbol gene ID | Definition Homo sapiens UDP-N- acteylglucosamine pyrophosphorylase UAP1L1 91.373 1-like 1 (UAP1L1) Homo sapiens egl nine homolog 1 (C. EGLN1 54583 eledans) (EGLN1 Homo sapiens ras homolog gene RHOU 58480 family Homo sapiens chemokine (C-X-C motif) ligand 6 (granulocyte CXCL6 6372 chemotactic protein 2) Homo sapiens delta-like 1 (Drosophila) DLL1 285.14 (DLL1) Homo sapiens protein tyrosine PPFIA4 8497 phosphatase Homo sapiens chemokine (C-C motif) CCL2 6347 lidand 2 (CCL2 one lightHomo polypeptide Sapiens nuclear gene enhancerfactor of kappa in B NFKBA O.912 2.5E-02 4792 Cells inhibitor Homo sapiens fibroblast growth factor FGF11 2256 11 (FGF11) Homo sapiens pleckstrin homology-like PHLDB2 90102 domain Homo sapiens chemokine (C-X-C CXCL2 2920 motif) ligand 2 (CXCL2) CYR6 3491 Homo sapiens cysteine-rich Homo sapiens IGF-like family member GFL1 374918 1 (IGFL1 Homo sapiens zinc finger protein 395 ZNF395 55893 (ZNF395) SULF1 23213 | Homo sapiens sulfatase 1 (SULF1) Homo sapiens BTG3 associated BANP 54971 nuclear protein (BANP) Homo sapiens YEATS domain YEATS2 55689 containing 2 (YEATS2) ZMZ 57.178 Homo sapiens Zinc finger Homo sapiens cell division cycle 25 CDC25B 994 homolod B (S. Oombe) (CDC25B RASL11B 65997 || Homo Sapiens RAS-like WANGL2 57216 Homo Sapiens vand-like 2 (van Coch Homo sapiens inhibitor of DNA binding D2 1.185 1.3E-02 3398 2 Homo sapiens serine/threonine-protein MGC42105 1.198 1.4E-O7 167359 kinase NIM1 (MGC42105) Homo sapiens inhibitor of DNA binding D 1.247 4.4E-02 3397 || 1 Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 40 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez symbol change p-value gene ID | Definition Homo sapiens solute carrier family 2

SLC2A1 1.297 6.3E-05 6513 (facilitated Olucose tranSOOrter RGS4 1.325as asso35E-04 sees5999 SidnallindR. 4 (RGS4R.S."" PLAU 5328 Homo sapiens plasminogen activator Homo sapiens cyclin-dependent kinase CDKN1C inhibitor 1C (p57 Homo sapiens N-myc downstream NDRG1 redulated Cene 1 (NDRG1 ENO2 5. OE-1 2026. Homo sapiens enolase 2 (gamma Homo sapiens 6-phosphofructo-2- PFKFB4 4.2E-07 521 Okinase/fructose-2 Figure 5 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 41 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez symbol change p-value gene ID | Definition PREDICTED: Homo sapiens similar to LOC728454 -3.059 2.2E-O5 728454 Beta-defensin 2 precursor (BD-2 DEFB4 -2.951 7.5E-27 1673 Homo sapiens defensin Homo sapiens matrix metallopeptidase MMP3 - 1903 1.3E-03 4314 || 3 (stromelysin 1 STC1 -1.78O 16E-34 6781 || Homo sapiens stanniocalcin 1 (STC1) Homo sapiens heat shock 70kDa HSPA1A - 1762 6.1E-24 3303 protein 1A (HSPA1A) DEFB 103A - 1596 1.9E-03 55894 | Homo sapiens defensin KIAA1199 - 1552 12E-11 57214 || Homo sapiens KIAA 1199 (KIAA 1199) Homo sapiens chromosome 7 open C7orf68 - 1532 4.2E-03 29923 reading frame 68 (C7orf68) Homo sapiens chemokine (C-C motif) CCL20 - 1503 1.5E-05 6364 idland 20 (CCL20 PPP1R3C -1477 3.9E-05 5507 || Homo sapiens protein phosphatase 1 Homo sapiens Small proline-rich protein SPRR2A - 1451 OE-12 6700 2A (SPRR2A Homo sapiens chromosome 1 open C1 Orf63 -1.348 1.7E-16 57035 reading frame 63 (C1 onfes3) Homo sapiens carbohydrate (N- acetylglucosamine 6-O) CHST7 - 1.169 5.7E-11 56548 Sulfotransferase 7 (CHST7 L13RA2 - 1.167 1.7E-02 3598 || Homo sapiens interleukin 13 receptor Homo sapiens S100 calcium binding S100A12 - 1,134 11E-03 6283 protein A12 (S100A12) IL1A - 1130 2.4E-O7 3552| Homo sapiens interleukin 1 Homo sapiens prostaglandin PTGS2 - 1.126 6.5E-12 5743 endoperoxide synthase 2 Homo sapiens Sin3A-associated SAP3O -1.087 4.7E-OS 8819 protein STC2 - 1025 1.3E-12 8614 || Homo sapiens stanniocalcin 2 (STC2) Homo sapiens matrix metallopeptidase MMP7 - 102O 8.8E-O9 4316 7 (matrilysin PLN2 - 1017 2.OE-03 123 Homo Sabiens OeriiOin 2 PLN2 Homo sapiens heat shock 70kDa HSPAB - 1014 1.5E-07 3304 protein B (HSPA1B) Homo sapiens PHD finger protein 13 PHF13 - 1013 6.4E-3 148479 (PHF13) Homo sapiens small proline-rich protein SPRR3 -O.999 1.9E-14 67O7 3 (SPRR3 NFL3 -O.992 3.9E-05 4783 || Homo sapiens nuclear factor Homo sapiens dehydrogenase/reductase (SDR family) DHRS9 -O.981 15E-02 10170 member 9 (DHRS9)

Figure 6 Patent Application Publication Aug. 6, 2015 Sheet 42 of 60 US 2015/0217131 A1

Gene fold Entrez SVnbol Chance O-Value Gene ID | Definition Homo sapiens epidermal growth factor EPS8 -O.972 4.4E-O2 receptor pathway substrate 8 (EPS8) L6 -O.969 5.OE-12 Homo sapiens interleukin 6 (interferon Homo sapiens LIM and cysteine-rich LMCD1 -O.955 6.OE-05 domains 1 (LMCD1) KIAAO907 -O.941 1.OE-03 Homo sapiens KIAAO907 (KIAAO907) Homo sapiens Rho-related BTB domain RHOBTB3 -O.915 1.6E-08 Containino. 3 (RHOBTB3 Homo sapiens transforming growth TGFBI -O.905 8.3E-05 factor Homo sapiens late cornified envelope LCE3D -0.890 1.8E-02 3D (LCE3D) CD55 -O.888 6.8E-04 Homo sapiens CD55 molecule Homo sapiens fibronectin type III FNDC3A -O.887 9.9E-08 domain Containing 3A (FNDC3A Homo sapiens thrombospondin 1 THES -O.882 5.5E-06 7057 (THES1) Homo sapiens tissue factor pathway TFP2 -0.871 4.2E-04 7980 inhibitor 2 (TFPI2) Homo sapiens dual specificity DUSP1 -O.861 4.4E-07 1843 phOSohatase 1 (DUSP1 Homo sapiens DNA-damage-inducible DDT4 -O.857 16E-10 transcript 4 (DDT4) AB3BP -O.853 8.OE-05 Homo sapiens AB gene family ZFP36L1 -O.849 | 1.4E-O3 Homo sapiens zinc finger protein 36 NT5E -0.849 4.1E-06 Homo sapiens 5'-nucleotidase Homo sapiens insulin-like growth factor IGFBP5 -O.837 4.8E-12 binding Orotein 5 (IGFBP5 Homo sapiens retinoic acid receptor responder (tazarotene induced) 2 RAR RES2 -O.831 2.5E-06 5919 (RARRES2) Homo Sapiens guanine nucleotide GNG11 -O.829 3.9E-O2 2791 binding protein (G protein) Homo sapiens cyclin-dependent kinase CDKN1B -0.823 6.OE-04 1027 inhibitor 1B (p27 Homo sapiens peptidase inhibitor 15 P15 -O.818 4.4E-O2 51050 (P15) Homo sapiens similar to C367G8.3 LOC441743 -O.818 7.3E-O3 441743 (novel protein similar to RPL23A) ACTA2 -0.87 44E-07 59 Homo sapiens actin Homo sapiens late cornified envelope LCE3E -O.814 | 1.4E-03 353145 3E (LCE3E MYL9 -O.805 1.2E-03 10398 Homo sapiens myosin SLC16A3 -O.805 6.3E-06 9123 Homo sapiens solute carrier family 16 Figure 6 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 43 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez symbol change p-value gene ID | Definition DNAJB9 -O.802 4.1E-O6 4189Homo sapiens DnaJ (Hsp40) homolog Homo sapiens CD163 molecule-like 1 CD 1631 -O.798 1.6E-03 283316 (CD163L1) Homo sapiens dihydropyrimidinase-like DPYSL3 -0.793 2.3E-05 1809 || 3 (DPYSL3) KRT27 -O.788 2.OE-03 342574 Homo sapiens keratin 27 (KRT27) SIX4 -O.787 2.7E-O4 51804 Homo sapiens SIX homeobox 4 (SIX4) Homo sapiens dipeptidyl-peptidase 4 DPP4 -O.784 8.7E-O7 1803 (DPP4) LCN2 -0.783 2.3E-O2 3934 || Homo sapiens lipocalin 2 (LCN2) Homo sapiens activated leukocyte cell ALCAM -O.782 4E-08 214 adhesion molecule (ALCAM) PLA2G4D -O.774 6.5E-04 283748 Homo sapiens phospholipase A2 Homo sapiens galectin-related protein HSPC159 -O.774 8.2E-O6 29094 (HSPC159) Homo sapiens armadillo repeat ARMCX2 -0.772 14E-O6 9823 Containino Homo sapiens Thy-1 cell surface THY -O.769 4.1E-09 7070 antigen (THY1) FTHL3 -O.766 2.OE-02 2498 Homo sapiens ferritin ACTG2 -O.765 2.9E-04 72 Homo Sapiens actin Homo sapiens phosphodiesterase 7B PDE7B -O.763 1.6E-O2 27115 (PDE7B) Homo sapiens transforming growth TGFBR3 -O.758 1.8E-08 7049 factor SEPT11 -O.754 1.6E-O2 55752 Homo Saoiens 11 SEPT11 LEP -O.754 1.2E-05 3952 Homo sapiens leptin (obesity homolog Homo sapiens Scavenger receptor cysteine-rich type 1 protein M160 M160 -O.753 2.9E-O2 28336 (M160) Homo sapiens vestigial like 3 VGLL3 -O.752 15E-02 389136 (Drosophila) (VGLL3) Homo sapiens fatty acid binding protein FABP3 -O.751 3.7E-O2 217O 3 Homo sapiens CCAAT?enhancer CEBPD -O.748 1.2E-08 1052 binding protein (C/EBP) Homo sapiens twist homolog 1 TWIST1 -O.748 1.2E-O7 7291 (Drosophila) (TWIST1) Homo sapiens secretory leukocyte SLP -O.746 3.2E-O5 6590 peptidase inhibitor (SLP Homo sapiens chromosome 13 open C13Of 15 -O.744 1.7E-O3 28984 reading frame 15 (C13orf15) Homo sapiens claudin 11 (oligodendrocyte transmembrane CLDN11 -O743 2.2E-O2 5010 protein) (CLDN11) Figure 6 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 44 of 60 US 2015/0217131 A1

Log 2 Gene fold symbol change Definition Homo sapiens alanyl (membrane) ANPEP -0.742 aminopeptidase (aminopeptidase N HIST1H1C -O.737 Homo sapiens histone cluster 1 SVEP1 -O.735 Homo Sapiens Sushi Homo sapiens Serpin peptidase SERPINF1 -0.731 5176 inhibitOr HIST1H4C -0.729 2.OE-04 8364 Homo Sapiens histOne Cluster 1 EGFL6 -O.725 25975 Homo sapiens EGF-like-domain Homo sapiens methionine sulfoxide MSRB2 -O.72O 4.6E-02 22921 reductase B2 (MSRB2 Homo sapiens egl nine homolog 3 (C. EGLN3 -0.718 112399 elegans) (EGLN3) Homo sapiens nicotinamide N NNMT -0.717 4837 methyltransferase (NNMT) Homo sapiens carbohydrate (N- acetylgalactosamine 4-sulfate 6-O) CHST15 -O.715 51363 Sulfotransferase 15 Homo sapiens reversion-inducing e cysteine-rich protein with kazal motifs RECK -O.71 O 1.9E-04 8434 (RECK easo Homo sapiens immediate early ER5L -O.709 6.4E-04 389792 resoOnSe 5-like (ER5L GREM1 -O.7O6 26585 Homo sapiens gremlin 1 VCAN -0.704 1462 | Homo sapiens versican (VCAN) Homo sapiens RAB3A interacting RAB3L1 -O.703 5866 protein (rabin3)-like 1 (RAB3L1) FLNC -O.701 2318| Homo sapiens filamin C LAMA4 -0.701 3910 | Homo sapiens laminin Homo sapiens zinc finger protein 512 ZNF512 -0.7OO 84.450 (ZNF512) Homo sapiens GLI pathogenesis GLIPR2 -0.696 152007 related 2 (GLIPR2) Homo sapiens G protein-coupled GPR124 -0.687 2596O receptor 124 (GPR124 RHOB -0.683 Homo sapiens ras homolog gene family Homo sapiens carboxypeptidase E CPE -0.682 (CPE) Homo sapiens R-spondin 3 homolog RSPO3 -O.682 Xenopus laevis) (RSPO3 PDE3B -O.682 5140 Homo sapiens phosphodiesterase 3B Homo sapiens heat shock HSPH1 -0.681 2.7E-04 10808 105kDa. OkDa protein 1 (HSPH1 assos Homo sapiens microfibrillar-associated MFAP4 -0.673 8.5E-03 4239 Orotein 4 (MFAP4 Figure 6 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 45 of 60 US 2015/0217131 A1

Log 2 Gene foo Errez symbol change p-value gene ID | Definition Homo Sapiens asparagine-linked ALG9 -0.67O 1.9E-05 79796 glycosylation 9 Homo sapiens anthrax toxin receptor 2 ANTXR2 -0.668 4.OE-04 118429 (ANTXR2 LAMC3 -0.668 1.4E-02 10319| Homo sapienslaminin Homo sapiens forkhead box Q1 FOXO1 -O.667 2.2E-O2 94234 (FOXO1) Homo sapiens chromosome 8 open C8orf13 -O.666 3.6E-O5 83648 reading frame 13 (C8orf13) IL1R1 -0.664 1.4E-O2 3554 || Homo sapiens interleukin 1 receptor Homo sapiens necdin homolog (mouse) NDN -0.663 1.7E-04 4692 (NDN) Homo sapiens family with sequence FAM43A -O.661 2.6E-O4 131583 Similarity 43 Homo sapiens myeloid/lymphoid or mixed-lineage leukemia (trithorax MLLT11 -0.655 2.1E-03 10962 homoloC LOX -0.654 8.6E-04 4015 Homo Sapiens VSV Oxidase (LOX ADM -0.652 6.2E-06 133 Homo Sapiens adrenomedulin (ADM Homo sapiens wingless-type MMTV WNT5A -O.650 2.7E-04 7474 integration site family Homo sapiens UDP-Gal:betaGlcNAc B4GALT5 -0.649 5.1E-O4 93.34 beta 1 COL4A1 -0.649 4.1E-06 1282 || Homo sapiens collagen Homo sapiens procollagen C PCOLCE -0.645 1.3E-O2 5118 endopeptidase enhancer (PCOLCE) Homo sapiens family with sequence FAM46A -0.644 3.3E-04 55603 || Similarity 46 Homo sapiens protein tyrosine PTPRG -0.642 2.8E-04 5793 phosphatase Homo sapiens teashirt zinc finger TSHZ3 -O.637 3.9E-O6 57616 homeobox 3 (TSHZ3) Homo sapiens matrix metallopeptidase MMP2 -0.635 3.3E-O2 4313| 2 (gelatinase A JUN -0.634 1.7E-O6 3725 | Homo sapiens jun oncogene (JUN) Homo sapiens fermitin family homolog FERMT2 -O.633 9.6E-O6 10979 2 (Drosophila) (FERMT2) Homo sapiens pregnancy-associated PAPPA -O.632 2.3E-O6 5069 plasma protein A Homo sapiens SERTA domain SERTAD2 -O.631 2.5E-04 9792 containing 2 (SERTAD2) Homo sapiens transmembrane protein TMEM42 -0.630 11E-O2 13161642 (TMEM42) Figure 6 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 46 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez SVimbol Chance O-Value Cere ID | Definition Homo sapiens UDP-N- acteylglucosamine pyrophosphorylase UAP1 -O.63O 1.2E-03 6675 1 (UAP1) PRKCA -0.6.29 31E-O3 5578 || Homo sapiens protein kinase C CALB2 -0.6.29 1.3E-O2 794 Homo Saoiens Calbindin 2 (CALE32 Homo sapiens complement component C1S -0.626 6.9E-03 716 || 1 Homo sapiens placental growth factor PGF -0.626 1.2E-02 5228 (PGF) Homo sapiens calcium/calmodulin dependent protein kinase II inhibitor 1 CAMK2N -0.626 6.OE-05 55450 (CAMK2N1 Homo sapiens ribosomal protein L23a RPL23AP13 -0.623 6.4E-03 56969 OSeudocene 13 (RPL23AP13 WASN -0.622 2.5E-06 114990 Homo sapiens vasorin (VASN) Homo sapiens FK506 binding protein FKBP11 -O.622 2.3E-O4 51303 11 PREDICTED: Homo sapiens tumor rejection antigen (gp96) 1 pseudogene TRAP2 -0.622 2.9E-02 343477 2 (TRA1P2) CD68 -0.622 1.OE-02 968 Homo sapiens CD68 molecule (CD68) Homo sapiens cytochrome c oxidase subunit Vila polypeptide 1 (muscle) COX7A1 -O.622 1.6E-O2 1346 (COX7A1) Homo sapiens cysteine-rich secretory protein LCCL domain containing 2 CRISPLD2 -O.621 7.OE-05 83716 (CRISPLD2 DNAJB1 -0.619 1.3E-02 3337 || Homo sapiens DnaJ (Hsp40) homolog SPON1 -O.619 3.7E-04 10418 Homo sapiens spondin 1 Homo sapiens chromobox homolog 6 CBX6 -0.6.16 68E-06 23466 (CBX6) TAGLN -0.6.16 21E-O2 6876 Homo sapiens transgelin (TAGLN) Homo sapiens Cbl-interacting protein STS-1 -0.615 6.5E-04 84.959 StS-1 (STS-1 Homo sapiens transmembrane protein TMEM47 -0.60 15E-04 836O4 47 (TMEM47 ZFAND2A -0.610 2.7E-06 90637 || Homo sapiens Zinc finger Homo sapiens SEC24 related gene SEC24D -0.61O 2.3E-04 9871 family Homo sapiens Schlafen family member SLFN11 -0.608 1.7E-03 91607 11 (SLFN11) Homo sapiens AE binding protein 1 AEBP -0.605 | 1.1E-02 165 (AEBP1) Homo sapiens phosphotyrosine PD1 -0.605 4.6E-03 55022 interaction domain containing 1 (PID1) Figure 6 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 47 of 60 US 2015/0217131 A1

Log 2 Gene fold Errez symbol change p-value gene ID | Definition Homo sapiens fatty acid desaturase 1 FADS1 -O.6O2 4.5E-02 3992 (FADS1) Homo sapiens DNA-damage-inducible DDT3 -O-6O2 2.3E-O5 1649 transcript 3 (DDT3) Homo sapiens TIMP metallopeptidase TIMP4 -O.6OO 1.5E-04 7079 inhibitor 4 (TIMP4) Homo sapiens myxovirus (influenza MX2 O.602 2.3E-05 4600 virus) resistance 2 (mouse) (MX2 Homo sapiens NIPA-like domain NIPAL1 O604 4.6E-O2 152519 containing 1 (NIPAL1) Homo sapiens E2F transcription factor E2F2 O611 3.7E-03 1870 2 (E2F2) AOP5 O612 11E-O2 362 Homo sapiens aduaporin 5 (AOP5 Homo sapiens TAR (HIV-1) RNA TARBP1 O614 2.3E-O2 6894 binding protein 1 (TARBP1) Homo sapiens vav 3 guanine VAV3 O618 2.7E-O2 10451 nucleotide exchange factor (VAV3) EXPH5 O.623 3.3E-O3 23086 || Homo sapiens exophilin 5 (EXPH5) Homo sapiens caspase recruitment CARD10 O.63O 3.OE-O2 29775 domain fami Homo sapiens receptor-interacting RPK4 O634 2.5E-03 54101 serine-threonine kinase 4 (RIPK4) Homo sapiens contactin associated CNTNAP2 O635 3.7E-O2 26047 protein-like 2 (CNTNAP2) Homo sapiens von Willebrand factor WWF O.638 S.OE-04 7450 (WWF Homo sapiens arachidonate 12 ALOX12 O.643 4.OE-O2 239 lipoxygenase (ALOX12) Homo sapiens glycerol kinase 5 GK5 O647 4.5E-02 256356 (putative) (GK5) SNORD36C O649 3.8E-O2 26813 Homo sapiens small nucleolar RNA SNORD31 O650 11E-O2 9298 || Homo sapiens small nucleolar RNA Homo sapiens LY6/PLAUR domain LYPD3 O653 2.2E-O4 27076 containing 3 (LYPD3) Homo sapiens psoriasis Susceptibility 1 PSORS1C2 O.656 1.3E-O2 170680 Candidate 2 (PSORS1 C2 Homo sapiens 2'-5'-oligoadenylate OAS2 O.656 3.OE-02 4939 synthetase 2 SNORA45 O66O 4.5E-03 677826 Homo sapiens small nucleolar RNA Homo sapiens chemokine (C-C motif) CCL27 O66O 3.OE-O2 1085Olidand 27 (CCL27 Homo sapiens tumor necrosis factor TNFRSF6B O662 4.1E-O3 87.71 receptor superfamily CAPNS2 O664 3.OE-1 84290 Homo sapiens calpain Figure 6 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 48 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez

s Vinbol Chance O-Value cene ID | Definition Homo sapiens sphingosine-1- S1PR5 0.665 1.5E-03 53637 phosphate receptor 5 (S1PR5) Homo sapiens family with sequence FAM46B 0.666 8.9E-04 115572 similarity 46 Homo sapiens lymphocyte antigen 6 LY6D O.668 4.OE-06 8581 complex Homo sapiens myosin regulatory light MYLIP O.668 1.9E-03 29116 chain interacting protein (MYLIP) SNORD100 O.669 2.4E-O2 594838 Homo sapiens small nucleolar RNA Homo sapiens poly (ADP-ribose) PARP12 O.67O | 1.4E-O7 64761 | polymerase family Homo Sapiens glutamic pyruvate transaminase (alanine GPT2 O.676 2.9E-02 84706 aminotransferase) 2 (GPT2) SLC4A11 O.677 1.5E-02 83959| Homo sapiens solute carrier family 4 Homo sapiens PYD and CARD domain PYCARD O.677 2.7E-05 291.08 containing (PYCARD) Homo sapiens interferon-induced F44L O.678 7.2E-05 10964 protein 44-like (IF|44L) Homo sapiens calmodulin-like 5 CALML5 O.684 1.2E-10 51806 (CALML5) COL17A1 O.688 11E-O2 1308| Homo sapiens collagen FETUB O.689 5.8E-03 26998 || Homo sapiens fetuin B (FETUB) Homo sapiens B-cell CLL/lymphoma BCL11B O.690 2.3E-O2 64919 11B (zinc finger protein) (BCL11B) WANGL2 O.694 2.2E-03 57216 Homo Sapiens vand-like 2 (Van OOC SNORD35B 0.695 2.2E-03 Homo sapiens small nucleolar RNA LGALS7 O.697 8.8E-35 Homo sapiens lectin Homo sapiens REC8 homolog (yeast) REC8 O.698 1.6E-O2 (REC8) Homo sapiens lysosomal-associated LAMP3 O.708 11E-O2 membrane protein 3 (LAMP3) Homo sapiens 7-dehydrocholesterol DHCR7 O.708 2.3E-04 reductase (DHCR7) CDH1 O.711 3.7E-02 Homo Saoiens Cadherin 1 Homo sapiens NYN domain and retroviral integrase containing NYNRIN O.714 4.3E-08 NYNRIN SNORD38A O.715 8.4E-03 94162 Homo sapiens small nucleolar RNA Homo Sapiens Squalene epoxidase SOLE O.717 5.4E-04 6713 (SQLE) Homo sapiens late cornified envelope LCE1 C O.718 9.8E-03 353133 1C (LCE1C) Figure 6 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 49 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez SWinbol Chance O-Walue gene ID | Definition Homo sapiens chromosome 18 open C18Orf45 O.718 1.4E-03 85019 reading frame 45 (C18orf45) Homo sapiens V-set and immunoglobulin domain containing 8 VSIG8 O.724 2.2E-04 391123 (VSIG8) Homo sapiens late cornified envelope LCE1E O.724 3.3E-O2 3531351E (LCE1E) PPK O.725 7.8E-03 64768 Homo Sapiens inositol 1 Homo sapiens LY6/PLAUR domain LYPD2 O.727 1.6E-04 137797 COntainino. 2 (LYPD2 Homo sapiens stearoyl-CoA desaturase SCD O.728 4.OE-09 6319 (delta-9-desaturase) (SCD Homo sapiens myxovirus (influenza MX1 O.732 1.6E-04 4599 virus) resistance 1 Homo sapiens proprotein convertase PCSK9 O.749 7.OE-03 255738 subtilisin/keyin type 9 (PCSK9) Homo sapiens plasma membrane PLLP O.755 1.5E-02 51090 proteolipid (plasmolipin) (PLLP) Homo sapiens late cornified envelope LCE1F O.756 4.9E-04 353 137 1F (LCE1F Homo Sapiens RAS guanyl releasing protein 1 (calcium and DAG-regulated) RASGRP1 O.76O 1.1E-04 101.25 (RASGRP 1) Homo sapiens leukotriene B4 receptor LTB4R2 O.762 4.9E-03 564,132 (LTB4R2) TECR O.764 3.5E-03 9524 Homo Sapiens trans-2 Homo sapiens hect domain and RLD 6 HERC6 O.77O 18E-07 55OO8 (HERC6 CYP2J2 O.776 2.OE-03 1573 || Homo sapiens cytochrome P450 Homo sapiens nuclear factor (erythroid NFE2 O.776 9.8E-03 4778 derived 2 Homo Sapiens Synaptotagmin-like 1 SYTL O.78O 3.8E-03 84958 (SYTL1 Homo sapiens phosphoinositide-3- PIK3C2B O78O 4.3E-O4 5287 kinase PRKY O.783 3.5E-04 5616 || Homo sapiens protein kinase Homo sapiens EPH receptor A1 EPHA O.786 2.3E-04 2041 (EPHA1) Homo sapiens deoxyribonucleasel-like DNASEL3 O.789 2.2E-03 1776 3 (DNASE1L3) ITGAM O.791 1.1E-04 3684 Homo Sapiens intedrin Homo sapiens iroquois homeobox 4 IRX4 O.791 5.7E-03 50805 (IRX4) Figure 6 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 50 of 60 US 2015/0217131 A1

Log 2 Gene fold Erez symbol change p-value gene ID | Definition Homo sapiens sterol regulatory element SREBF1 O.794 1.7E-O4 6720 binding transcription factor 1 (SREBF1) Homo sapiens troponin | type 2 TNN2 O.798 8.1E-03 7136 (skeletal Homo sapiens DNA segment on chromosome 4 (unique) 234 expressed D4S234E O.805 8.2E-O4 27O65 Secuence (D4S234E Homo sapiens family with sequence FAM83B O.808 16E-03 222584 similarity 83 CYP4F12 O.812 1.9E-03 66002 || Homo sapiens cytochrome P450 Homo sapiens E74-like factor 5 (ets ELF5 O.815 5.9E-03 2001 | domain transcription factor) (ELF5) Homo sapiens neuroblastoma NBPF20 O816 2.OE-05 40O818 breakOoint famil Homo sapiens POU class 3 homeobox POU3F1 O.818 98E-O4 5453 1 (POU3F1) LPM O.823 8.2E-05 34O654 || Homo sapiens lipase Homo sapiens chromosome 3 open C3orf52 O.824 4.6E-O6 79669 reading frame 52 (C3orf52 Homo sapiens transmembrane protein TMEM184A O.827 94E-04 202915 184A (TMEM184A) KCNK7 O.829 4.1E-O4 1.0089 Homo sapiens potassium channel ATP6V1C2 O.831 5.3E-O8 245973 || Homo sapiens ATPase Homo sapiens chromosome 15 open C15Orf59 O.832 2.7E-O4 388135 reading frame 59 (C15orf59) Homo sapiens calmodulin-like 3 CALML3 O.836 8.8E-35 810 (CALML3) Homo sapiens achaete-scute complex ASCL2 O.836 2.7E-04 430 homolog 2 (Drosophila) (ASCL2) RAB7B O.839 3.9E-06 338382 Homo sapiens RAB7B Homo sapiens mevalonate (diphospho) MVD O.844 14E-04 4597 decarboxylase (MVD Homo sapiens aduaporin 3 (Gill blood AOP3 O.845 6.6E-O4 360 Group) (AOP3 Homo sapiens 5-hydroxytryptamine HTR3A O847 2.6E-O2 3359 (serotonin) receptor 3A (HTR3A) Homo sapiens bone marrow stromal BST2 O847 7.5E-06 684 cell antigen 2 (BST2) CYP2C18 O.858 8.OE-04 1562 || Homo sapiens cytochrome P450 Homo sapiens plakophilin 1 (ectodermal dysplasia/skin fragility PKP 1 O.864 3.7E-O2 5317 SWCrome) (PKP1 CTNNBP1 O.864 11E-19 56998 || Homo sapiens catenin

Figure 6 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 51 of 60 US 2015/0217131 A1

Log 2 Gene fold Eritrez symbol change p-value gene ID | Definition SLC16A10 O865 68E-03 117247 || Homo Sapiens Solute Carrier family 16 PLAU O869 7.1E-04 5328 Homo sapiens plasminogen activator Homo sapiens hairy and enhancer of HES2 0.883 5.7E-03 54626 Split 2 (DroSOohila) (HES2 Homo sapiens family with sequence FAM83C O.885 14E-O3 128876 similarity 83 Homo sapiens FAT tumor suppressor FAT2 O.891 4.1E-06 21.96 homolog 2 (Drosophila) (FAT2) CDH3 O891 5.4E-04 1001 | Homo Sapiens Cadherin 3 Homo sapiens aldo-keto reductase AKR1B15 O.892 | 1.4E-06 44.1282 family 1 BNC1 O.894 2.4E-03 646 | Homo sapiens basonuclini (BNC1) Homo sapiens EPH receptor B6 EPHB6 O898 3.9E-06 2051 (EPHB6) Homo sapiens fatty acid synthase FASN O.906 8.8E-35 2194 (FASN) Homo sapiens 3-hydroxy-3- methylglutary-Coenzyme A synthase 1 HMGCS1 0.907 8.5E-06 3157 (Soluble) (HMGCS1 Homo sapiens CCAAT?enhancer CEBPA O907 34E-04 1050 bindino Orotein (C/EBP Homo sapiens nucleotide-binding oligomerization domain containing 2 NOD2 0.913 3.6E-03 64 127 (NOD2) F27 O.924 3.3E-O7 3429 || Homo sapiens interferon Homo sapiens interferon-induced protein with tetratricopeptide repeats 3 FIT3 O.924 6.1E-13 3437 (FIT3 KRT13 O929 3.OE-04 3860 Homo sapiens keratin 13 (KRT13) Homo sapiens tumor necrosis factor TNFSF10 O965 2.6E-O6 8743 (ligand) superfamily Homo sapiens zinc finger and BTB ZBTB7C O965 3.9E-05 201501 domain containing 7C (ZETB7C) Homo sapiens kinesin family member KFC2 O.97O 1.6E-08 90990 C2 (KFC2) Homo sapiens protein tyrosine PTPRZ1 0.971 1.3E-08 5803 phosphatase Homo sapiens serum/glucocorticoid SGK O.989 1.OE-06 6446 regulated kinase (SGK) ANO9 O.996 1.2E-05 338440 Homo sapiens anoctamin 9 (ANO9) Homo sapiens late cornified envelope LCE1B 0.999 || 1.OE-07 353132 1B (LCE1B) Homo sapiens asialoglycoprotein ASGR1 1.018 5.8E-07 432 receptor 1 (ASGR1) Homo sapiens tumor protein p53 TP53INP2 1.019 2.OE-08 58476 inducible nuclear protein 2 (TP53INP2) Figure 6 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 52 of 60 US 2015/0217131 A1

Log 2 Gene fold Entrez symbol change p-value gene ID | Definition Homo sapiens interferon-induced protein with tetratricopeptide repeats 1 FT1 1.050 8.8E-35 3434 (IFT1 THBD 1.052 2.8E-O6 7056 || Homo sapiens thrombomodulin (THED) Homo sapiens aldo-keto reductase AKR1BO 1054 4.1E-06 57O6 family Homo sapiens serum/glucocorticoid SGK1 1.062 1.1E-O6 6446 redulated kinase 1 (SGK1 MSMB 1.066 2.4E-05 4477 Homo SapienS microSeminOOrotein Homo sapiens late cornified envelope LCE1A 1.076 1.3E-05 353131 1A (LCE1A) Homo sapiens keratin9 (epidermolytic KRT9 1.08O 15E-08 3857 | palmoplantar keratoderma) (KRT9) Homo sapiens leukotriene B4 receptor LTB4R 1.090 4.4E-O7 1241 (LTB4R) Homo sapiens internexin neuronal NA 1.098 2.9E-09 9118 intermediate filament protein Homo sapiens late cornified envelope LCE1D 1.126 6.OE-O6 3531 34 1D (LCE1D Homo sapiens fibroblast growth factor FGFR3 1.198 1.2E-04 2261 receptor 3 (achondroplasia Homo sapiens chromosome 10 open C10orf9 1.205 8.8E-35 387695 readinC frame 99 (C1 OOrfS9 Homo sapiens aldehyde dehydrogenase 2 family (mitochondrial) ALDH2 1.220 8.8E-35 217 (ALDH2) Homo sapiens radical S-adenosyl methionine domain containing 2 RSAD2 1.312 8.8E-35 91543 (RSAD2 Homo sapiens glutathione peroxidase 2 GPX2 1.338 8.8E-35 2877 (gastrointestinal) (GPX2) Homo sapiens IGF-like family member |GFL1 1517 6.OE-08 374918 1 (IGFL1 Homo sapiens chemokine (C-X-C motif) CXCL10 1.93 8.8E-35 3627 ligand 10 (CXCL10) Homo sapiens late cornified envelope LCE5A 2.141 8.8E-35 254910 5A (LCE5A) Figure 6 (cont.) Patent Application Publication Aug. 6, 2015 Sheet 53 of 60 US 2015/0217131 A1

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TERAHERTZ PULSE RADATION IN the skin of individuals afflicted with skin disorders such as TREATING SKINDSORDERS non-melanoma skin cancers, psoriasis and atopic dermatitis. 0010. Accordingly, the disclosure provides a means for RELATED APPLICATIONS modulating gene expression (e.g., in skin cells or in skin 0001. This application claims priority under 35 U.S.C. tissue) by providing a source of terahertz radiation, exposing S119(e) to U.S. Provisional Patent Application No. 61/936, skin cells or skin tissue to pulses of terahertz radiation in an 627, filed Feb. 6, 2014, which is incorporated herein by ref amount Sufficient to modulate gene expression where modu CCC. lation of gene expression results in a reduction of a disease state in the skin cells or skin tissue. BACKGROUND OF THE INVENTION 0011. In some embodiments, the terahertz radiation has a bandwidth of about 0.1 to about 10 terahertz, for example in 0002. Non-melanoma skin cancer (NMSC) and psoriasis some embodiments, about 0.2 to about 2.5 terahertz. are two skin conditions that affect a large number of individu 0012. In some embodiments, the pulse of terahertz radia als each year. In the United States alone, there are over 3.5 tion is about 0.2 to about 100 picoseconds, about 5 to about 15 million cases of NMSC while 1-3% of the population of the picoseconds, or about 10 picoseconds. United States will develop psoriasis in their lifetime. 0013. In some embodiments, the duration of exposure to 0003 NMSC can be primarily divided into two types of terahertz radiation can be about 1 minute to about 30 minutes. skin cancers: squamous cell carcinomas and basal cell carci In one specific embodiment, the duration of exposure to tera nomas. Basal cell carcinomas account for 80% of all NMSC hertz radiation can be about 10 minutes. cases. This type of cancer develops in cells in the lower 0014. In some embodiments, the pulses of terahertz radia epidermis. Such carcinomas occur most frequently on the tion have a pulse energy of about 0.01 to about 100 micro face, ears, neck, Scalp, shoulders, and back. Basal cell carci joules, about 0.1 to about 2.0 micro-joules, or about 1.0 noma is usually slow growing and rarely metastasizes, but it microjoule. can cause significant local destruction and disfigurement if neglected or treated inadequately. 0015. In some embodiments, the pulses of terahertz radia 0004. The remaining 20% of NMSC is squamous cell tion have a repetition rate of about 1 hertz to about 100 carcinoma. Squamous cell carcinoma develops in the upper megahertz. In one specific embodiment, the pulses of tera most layers of the epidermis. Of the over 700,000 new cases hertz radiation have a repetition rate of about 1 kilohertz. of Squamous cell carcinomas diagnosed each year in the 0016. In some embodiments, the pulses of terahertz radia United States, over 2,500 will result in death. tion are confined to a spot size of about 0.1 mm to 100mm. 0005 Psoriasis is a chronic immune mediated skin disor 0017. In another embodiment, the pulses of terahertz der effecting 1-3% of the population of the United States. radiation are raster scanned across a large area of the target Psoriasis is characterized by hyperplasia of keratinocytes (e.g., 100 mm to two, three, four, or five times this area). resulting in thickening of the epidermis and the presence of 0018. In some embodiments, the gene expression of the red scaly plaques. The lesions in this chronic disease typically skin cells is down-regulated, or alternatively, up-regulated. are subject to remissions and exacerbations. Some individu 0019. In some embodiments, the disease state is a skin als with psoriasis can also develop psoriatic arthritis and joint disorder. In one specific embodiment, the disease state is a pain. Moreover, psoriasis can also be a psychological burden skin disorder Such as psoriasis, atopic dermatitis, or other on those afflicted by the disease when the affected skin areas non-specific inflammatory skin conditions. In another are visible to others. embodiment the disease State is an inflammatory skin disease. 0006 Current treatment of NMSC generally involves sur In another embodiment the disease state is skin cancer. In gical excision of the tumor together with a margin of normal Some embodiments, the disease state is a non-melanoma skin tissue and, when Surgery is not feasible or desirable, destruc cancer. In other embodiments, the skin cancer is basal cell tion of the tumor cells by ionizing radiation or other means. carcinoma, squamous cell carcinoma, or other type of non Treatment for psoriasis involves topical applications, sys melanoma skin cancer. In another embodiment, the disease temic treatments (e.g., drug injections), and phototherapy state is atopic dermatitis. 0020. In various embodiments, therapeutic effect is involving exposure to UV radiation. achieved by modulating expression of specific disease-re 0007 Although each method of treatment can be relatively lated target genes. In some embodiments, exposure to pulsed effective, each has its drawback. For example, removal of a THZ radiation causes down-regulation of genes that are up NMSC patch can leave a visible scar. On the other hand, not regulated in diseased but not in healthy skin. In other embodi only is moderate to severe psoriasis resistant to topical treat ments, exposure to pulsed THZ radiation causes up-regulation ments, but because of its chronic and recurrent nature, sys of genes that are down-regulated in diseased skin compared to temic therapy or radiation is often required. healthy skin. In certain embodiments, at least one of the genes 0008. Therefore, there is a need for further methods of down-regulated is selected from the group consisting of treating skin disorders that are rapid, minimally invasive, S100P, S100A11, S100A12, S100A15, SPRR2A, SPRR3, specific for skin, and easy to use. SPRR1B, SPRR2B, SPRR2C, LCE3, LCE3D, CD24, DEFB103A, DEFB4, LOC728454, DEFB1, IVL SER SUMMARY PINB3, SERPINB4 and SERPINB13. In other embodiments, 0009. The disclosure provides for a method of using tera at least one of the genes up-regulated is selected from the hertz radiation as a means to modulate gene expression in skin consisting of LCE1A, LCE1B, LCE1C, LCE1D, LCE1 E. cells having an active skin disorder Such as psoriasis, atopic LCE1F and LCE5A. dermatitis or non-melanoma skin cancer. The disclosure also 0021. In another embodiment, there is disclosed a method provides methods of modulating gene expression through the for treating skin cancer comprising the steps of a method for application of intense, picosecond pulses of THZ radiation to treating a patient with skin cancer using terahertz radiation, US 2015/0217131 A1 Aug. 6, 2015 the method comprising the steps of providing a source of 0026 FIG. 4. Genes differentially expressed following terahertz radiation, exposing a patient to pulses of terahertz exposure to 1.0 LJ THZ pulses. radiation, wherein the pulses of terahertz radiation have a (0027 FIG. 5. Genes differentially expressed following bandwidth of about 0.2-2.5 terahertz, a pulse energy of about exposure to 0.1 LJ THZ pulses. 0.1-1.0 microjoules for about 30 minutes, the exposure to the 0028 FIG. 6. Genes differentially expressed following terahertz radiation being in an effective amount to induce at exposure to UVA (0.024. LJ 400 nm) pulses. least a 1.5 fold change in gene expression in the skin cancer (0029 FIG. 7. Differentially expressed EDC genes and cells as compared to a control sample not exposed to terahertz selected other genes associated with non-melanoma skin can radiation; and where the change in gene expression results in cer or inflammatory skin diseases, as shown in FIGS. 3b and a reduction in the level of skin cancer in the patient. 3C. 0030 FIG.8. RNA expression measured for differentially BRIEF DESCRIPTION OF THE DRAWINGS expressed EDC genes and selected other genes associated with non-melanoma skin cancer or inflammatory skin dis 0022. The following drawings form part of the specifica eases. (a) Replicates, mean values and standard deviations for tion and are included to further demonstrate certain embodi control and 1.0 LJ THZ pulse-exposed tissues. Symbols of ments or various aspects of the invention. In some instances, up-regulated genes are highlighted in red, down-regulated embodiments of the invention can be best understood by genes in green, and unaffected genes are shown in black. (b) referring to the accompanying drawings in combination with Replicates, mean values and standard deviations for control the detailed description presented herein. The description and and 0.1 LJ THZ pulse-exposed tissues. Symbols of up-regu accompanying drawings may highlight a certain specific lated genes are highlighted in red, down-regulated genes in example, or a certain aspect of the invention. However, one green, and unaffected genes are shown in black. (c) Repli skilled in the art will understand that portions of the example cates, mean values and standard deviations for control and or aspect may be used in combination with other examples or UVA-exposed tissues. Symbols of up-regulated genes are aspects of the invention. indicated as red (“IR” after the Gene symbol), down-regu 0023 FIG.1. Intense THz pulses and skin tissue samples lated genes are indicated as green (“IGI after the Gene sym used in this study. (a) Electric field waveform of the THz bol), and unaffected genes are shown in black (all others not pulse. (b) Spectral bandwidth of the THz pulse shown in A. (c) marked with R or G after the Gene symbol). THZ spot profile at the focus. The 1/e2 diameter of the THz beam is 1.5 mm. The 2 mm-diameter dashed circle shows the DETAILED DESCRIPTION portion of the tissue that was excised for gene profiling. (d) 0031. Non-melanoma skin cancer (NMSC) and psoriasis Histology of an EpiDermFT tissue section (400x image, are skin disorders that affect a large portion of the population courtesy of Mattek). (e) Schematic illustration of the THz globally. NMSC affects about 3.5 million individuals in the exposure procedure. The EpiDermFT tissue is in a single well United States alone, while psoriasis affects between 1-3% of insert placed at the focus of THZ beam. the population of the United States. Current methods for 0024 FIG. 2. Intense THz-pulse-induced gene expression treating these skin disorders include topical applications, sys in human skin. Venn diagrams Summarizing differentially temic application, radiation therapy, UV radiation or skin expressed genes in EpiDermFT tissues exposed to either 1.0 removal. Unfortunately, each of these methods has disadvan LJ or 0.1 LJ THz or UVA (400 nm, 0.024 LJ) pulses, as tages such as pronounced side effects or scaring. Therefore, described in Materials and Methods. Genes with a False Dis there is a need for a method to overcome these difficulties. covery Rate (FDR)-adjusted p-value <0.05 and log 2 fold 0032 Broadband terahertz (THz) radiation resides change >0.6 (1.5x change) were considered differentially between the infrared and microwave wavelengths (0.1-10 expressed. Left diagram: down-regulated genes. Right dia THz) of the electromagnetic spectrum. THZ photons are low gram: up-regulated genes. The complete lists of the affected energy, with photon energies typically between 0.5 and 15 genes, the fold change and p-values are given in FIG. 4, FIG. meV, and therefore represent radiation. This is in contrast to 5 and FIG. 6. ionizing radiation Such as Ultra-violet radiation, having high 0025 FIG. 3. Differentially expressed Epidermal Differ energy photons around 3.0 eV. Ionizing radiation exerts det entiation Complex (EDC) genes and selected other genes rimental effects on living cells by breaking chemical bonds in associated with non-melanoma skin cancer or inflammatory DNA and other biological molecules. The non-ionizing skin diseases. (a) EDC genes that were either up-regulated nature of THZ radiation makes it a useful tool in clinical (green rectangles) or down-regulated (red rectangle) after applications. Accordingly, ultrafast lasers emitting THZ exposure of skin tissues to either 1.0LJ or 0.1 LJ THZ pulse radiation have been used as non-invasive tools for cancer energies, or UVA pulses. Unaffected genes are depicted as diagnosis, intra-operative tumor margin identification, burn white rectangles. (b) log 2 fold changes for differentially assessment, and in vivo skin and cornea hydration sensing. expressed genes belonging to four families of EDC genes 0033 Although THZ radiation can have thermal effect on (FLG-like, LCE. 5100, and SPRR). (c) Other genes (selected) biological tissue due to absorption of the radiation by water, involved in dermatological diseases and cancer, whose Such effects are typically limited to instances of continuous expression levels were altered by exposure to both THZ pulse wave excitation. More recent theoretical modeling and other energy regimes. In (b) and (c), error bars indicate correspond experiments suggest many important biomolecules (e.g., ing standard deviations, and in Some cases are Smaller than nucleic acid, ) have intrinsic vibrational resonances the symbol size. Mean values, log 2 fold changes relative to in the THz range. It is thought that resonant coupling of THz control mean values, and FDR-adjusted p-values for genes in radiation with the intrinsic vibrational modes of biomolecules (b) and (c) are given in FIG. 7. Individual replicates, mean may affect the conformational state of the biomolecule, values and corresponding standard deviations are given in thereby impacting cellular function. Moreover, THZ radiation FIG 8. only penetrates the human body to a depth of a few millime US 2015/0217131 A1 Aug. 6, 2015

ters, thereby avoiding any irradiation of vital organs. These 0039. In some embodiments, the total exposure to THz characteristics make THz radiation ideal for the treatment of radiation pulses can be about, 1-120 minutes, or about 1-60 skin disorders. minutes, about 1-30 minutes and preferably about 2-10 min 0034. Described herein is a method for treating skin dis utes. orders including, but is not limited to the steps of: 1) provid 0040. In still further embodiments, the energy density per ing a source of terahertz radiation, 2) exposing skin cells to pulse of THz radiation can be about 6 microjoules/cm for a pulses of THZ radiation and 3) modulating the gene expres 0.1 microjoule THz pulse and about 60 microjoules/cm for a sion to cause a reduction of a disease state, or prevent an 1 microjoule THz pulse. increase in the disease state in the skin cells. 0041. The application of THZ radiation to the skin cells 0035. In a more specific embodiment, there is provided a can modulate gene expression (up-regulation or down-regu method for treating skin cancers that includes the steps of lation) in the area of exposure. Although the mechanism for exposing a patient to a source of terahertz radiation wherein this action is not entirely known, THZ radiation is thought to the pulses of terahertz radiation have a bandwidth of about cause conformational changes in the cellular machinery. For 0.2-2.5 terahertz, a pulse energy of about 0.1-1.0 microjoules example, THZ pulses can cause local melting (AKA breath and an exposure time of about 30 minutes. The exposure to ing) of double-stranded nucleic acid, thereby facilitating gene the terahertz radiation is sufficient to induce at least a 1.5 fold transcription. THZ radiation can also cause the activation or change in gene expression in the skin cancer cells as com repression of transcription factors by inducing a conforma pared to a control sample not exposed to terahertz radiation, tion change in various proteins, thereby allowing or disrupt resulting in a reduction in the level of skin cancer in the patient. ing interaction with other biomolecules. 003.6 THZ radiation can be generated by any method 0042 Generally, picosecond THZ radiation pulses have known to one skilled in the art such as but not limited to Far been shown to down-regulate genes involved in inflammatory Infrared Lasers, Quantum Cascade Lasers and Free electron skin disorders and cancers such psoriasis, atopic dermatitis, Lasers. Furthermore, terahertz radiation can be generated epidermal hyperplasia, dermatitis, oral squamous cell carci using a Ti:Saphire femtosecond lasers that are directed into an noma and non-melanoma skin cancer (squamous cell carci electro-optic crystal Such as a Zinc blend crystal (e.g., Zinc noma and basal cell carcinoma). A non-exhaustive list of telluride crystal, gallium arsenide crystal) or lithium crystals genes affected by THZ radiation is listed in FIG. 4 and FIG.5. Such as lithium niobate. In another approach, a photoconduc As used herein, a gene is considered to be up-regulated or tive dipole antenna can be used. In a further embodiment, down-regulated due to THZ radiation exposure if the gene terahertz radiation can be obtained by mixing multiple emis shows a change in expression levels of at least about 1.5-fold sions from near-infrared diode lasers. Other sources of THZ or greater when compared to a control sample. Alternatively radiation include backward wave oscillators, gyrotrons, in the method, a statistical difference of about two standard Gunn diodes, frequency multiplier units based on Schottky deviations or more from the mean is considered significant Barrier diodes, impact ionization avalanche transit-time upon comparing control and test samples. devices (IMPATTs), tunneling transit time diodes (TUN 0043 Among those genes down-regulated are members of NETT), and resonant tunneling diodes. Preferably, the source the Epidermal Differentiation Complex (EDC) genes located of THZ radiation is hand held or capable of being set up on a on human chromosome 1 q21 (see FIG. 3). The EDC com bench top. Generally, the source of THZ radiation is held or prises 57 genes encoding 5100 proteins as well as structural positioned in close proximity to the sample to be treated. In proteins of epidermal cornification. Many of these genes are some embodiments, the source of THZ radiation is positioned up-regulated in skin disorders such psoriasis, atopic derma so that the radiation beam covers a spot size of about 1.5 mm titis and skin cancers. These genes include members of the to about 2 mm. In other embodiments, larger or Smaller areas Small Proline Rich Region (SPRR), Late Cornified Envelope can be subject to the THz radiation with spot diameters, for (LCE), Involucrin (IVL), NICE-1, Cornulin (CRNN) and example of 0.1, 5, 10, 100, 1000, 10000 fold the diameter of S100. At least 16 members of these families, known to be the above referenced spot size (1.5-2 mm). up-regulated in psoriasis, are down-regulated in response to 0037. In some embodiments, the skin cells, tissue or THZ radiation. These include, but are not limited to S100A15, patient are subjected to pulses of THZ radiation. The duration S100A12, SPRR2A, SPRR3, SPRR2B, SPRR3, SPRR4, of THZ pulses can be about 1-15 picoseconds, preferably SPRR1B, SPRR2D, SPRR2E, SPRR2F, SPRR2C, LCE3A, about 1-10 picoseconds, more preferably about 1-5 picosec LCE2D, LCE3D and LCE3. Other genes down-regulated by onds and even more preferably about 1 picosecond. More THZ radiation and implicated in psoriasis are corneodesmo over, in Some embodiments, the range of THZ radiation can sin (CDSN), CD24, members of the human B-defensin family range between 0.1-10 THz, preferably about 0.1-5THZ and (DEFB103A, DEFB4, LOC728454 and DEFB1), and mem more preferably about 0.2-2.5 THz. In other embodiments, bers of the serine protease inhibitor (serpin) B genes includ the repetition rate for THZ pulses is generally about 1-100000 ing serpinB3, serpinB4 and serpinB13. Up-regulation of kilohertz, about 1-50000 kilohertz, about 1-10000 kilohertz, B- is also implicated in basal cell carcinomas. about 1-1000 kilohertz, about 1-500 kilohertz, about 1-100 0044 EDC genes, among others, are also up-regulated in kilohertz, about 1-50 kilohertz, or about 1 kilohertz. cutaneous squamous cell carcinomas. Of these, at least 8 0.038. In some embodiments, pulse energies may range genes are down-regulated by exposure to THZ radiation. between 0.1-100 microjoules, and preferably about 0.1-10 These include including S100A11, S100A12, SPRR1B, microjoules, and more preferably about 0.1-2 microjoule, and SPRR2B, SPRR2C, SPRR3, IVL, and LCE3D. Other genes even more preferably about 0.1-1.0 microjoules. In further down-regulated by THZ radiation involved in squamous cell embodiments, the THz radiation can have a peak electric field carcinomas include CD24, DEFB103A, DEFB4, of about 220 kV/cm for a 1.0 microjoule pulse energy and LOC728454, DEFB1, serpinB3, serpinB4 and serpinB13 about 70 kV/cm for a 0.1 microjoule pulse energy. (also see FIG. 7 and FIG. 8). US 2015/0217131 A1 Aug. 6, 2015

0045. Furthermore, the EDC gene S100P is known to be these purposes normally means sequence identity of at least up-regulated in many tumor types, acting as a proliferative 70%, 80%, 90%, or even at least 95%. and anti-apoptotic agent. Moreover, disruption of the S100P 0051. Another indication that nucleotide sequences are gene is known to Suppress the growth of hepatocellular car substantially identical is if two molecules hybridize to each cinoma cells. S100P is down-regulated when exposed to THz other under Stringent conditions. Generally, stringent condi radiation. tions are selected to be about 5° C. lower than the thermal 0046. In some situations, EDC genes may be down-regu melting point (T) for the specific sequence at a defined ionic lated in certain disease states. Some of these genes known to strength and pH. However, stringent conditions encompass be down-regulated in a certain disease state include, but are temperatures in the range of about 1° C. to about 20° C. not limited to LCE1A, LCE1B, LCE1C, LCE1D, LCE1 E, depending upon the desired degree of stringency as otherwise LCE1F and LCE5A. Exposure to THZ radiation may result in qualified herein. Nucleic acids that do not hybridize to each up-regulation of these genes, leading to a decrease in the other under stringent conditions are still Substantially identi disease state (also see FIGS. 4-6 for a list of genes that are cal if the polypeptides they encode are substantially identical. up-regulated in response to THZ radiation). This may occur, e.g., when a copy of a nucleic acid is created 0047. In some embodiments, the THz radiation is applied using the maximum codon degeneracy permitted by the to a human patient. In other embodiments, the THz radiation genetic code. One indication that two nucleic acid sequences may be applied to human skin tissue, artificial human skin are substantially identical is when the polypeptide encoded tissue, or evenanimal skin tissue to modulate gene expression by the first nucleic acid is immunologically cross reactive leading to a reduction, or at least prevent an increase in a with the polypeptide encoded by the second nucleic acid. disease state. 0052. The term “substantial identity” in the context of a 0048. In addition, THZ radiation may modulate genes and peptide indicates that a peptide comprises a sequence with at proteins sharing a sequence identity or Substantial sequence least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, identity to those genes and proteins listed herein. 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 0049. As used herein, “sequence identity” or “identity” in 89%, 90%, 91%, 92%, 93%, or 94%, or even 95%,96%, 97%, the context of two nucleic acid or protein sequences makes 98% or 99%, sequence identity to the reference sequence over reference to a specified percentage of residues in the two a specified comparison window. In certain embodiments, sequences that are the same when aligned for maximum cor optimal alignment is conducted using the homology align respondence over a specified comparison window, as mea ment algorithm of Needleman and Wunsch (Needleman and sured by sequence comparison algorithms or by visual Wunsch, JMB, 48, 443 (1970)). An indication that two pep inspection. When percentage of sequence identity is used in tide sequences are substantially identical is that one peptide is reference to proteins it is recognized that residue positions immunologically reactive with raised against the which are not identical often differ by conservative amino second peptide. Thus, a peptide is substantially identical to a acid substitutions, where amino acid residues are substituted second peptide, for example, where the two peptides differ for other amino acid residues with similar chemical proper only by a conservative substitution. Thus, the invention also ties (e.g., charge or hydrophobicity) and therefore do not provides nucleic acid molecules and peptides that are Sub change the functional properties of the molecule. When stantially identical to the nucleic acid molecules and peptides sequences differ in conservative Substitutions, the percent presented herein. sequence identity may be adjusted upwards to correct for the 0053 For sequence comparison, typically one sequence conservative nature of the substitution. Sequences that differ acts as a reference sequence to which test sequences are by Such conservative Substitutions are said to have “sequence compared. When using a sequence comparison algorithm, similarity” or “similarity.” Means for making this adjustment test and reference sequences are input into a computer, Sub are well known to those of skill in the art. Typically this sequence coordinates are designated if necessary, and involves scoring a conservative Substitution as a partial rather sequence algorithm program parameters are designated. The than a full mismatch, thereby increasing the percentage sequence comparison algorithm then calculates the percent sequence identity. Thus, for example, where an identical sequence identity for the test sequence(s) relative to the ref amino acid is given a score of 1 and a non-conservative erence sequence, based on the designated program param Substitution is given a score of Zero, a conservative substitu eters. tion is given a score between Zero and 1. The scoring of conservative Substitutions is calculated, e.g., as implemented DEFINITIONS in the program PC/GENE (Intelligenetics, Mountain View, Calif.). 0054 The following definitions are included to provide a 0050. The term “substantial identity” of polynucleotide clear and consistent understanding of the specification and sequences means that a polynucleotide comprises a sequence claims. As used herein, the recited terms have the following that has at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, meanings. All other terms and phrases used in this specifica 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, tion have their ordinary meanings as one of skill in the art 88%, 89%, 90%, 91%, 92%, 93%, or 94%, or even at least would understand. Such ordinary meanings may be obtained 95%,96%.97%.98%, or 99% sequence identity, compared to by reference to technical dictionaries, such as Hawley's Con a reference sequence using one of the alignment programs densed Chemical Dictionary 14" Edition, by R. J. Lewis, described using standard parameters. One of skill in the art John Wiley & Sons, New York, N.Y., 2001. will recognize that these values can be appropriately adjusted 0055 As used herein, non-ionizing radiation refers to any to determine corresponding identity of proteins encoded by type of electromagnetic radiation that does not carry enough two nucleotide sequences by taking into account codon energy to completely remove an electron from an atom or degeneracy, amino acid similarity, reading frame positioning, molecule, and preferably has photon energy of between about and the like. Substantial identity of amino acid sequences for 0.5 meV and about 15 meV. US 2015/0217131 A1 Aug. 6, 2015

0056. As used herein, ionizing radiation refers to radiation persons skilled in the art. The term “effective amount” is that carries enough energy to liberate electrons from atoms or intended to include an amount of a compound described molecules, thereby ionizing them and generally consists of herein, or an amount of a combination of compounds gamma rays, X-rays, and the higher ultraviolet part of the described herein, e.g., that is effective to treat or prevent a electromagnetic spectrum. disease or disorder, or to treat the symptoms of the disease or 0057. As used herein, modulation of gene expression disorder, in a host. Thus, an “effective amount generally refers to changing the level of expression of ageneata certain means an amount that provides the desired effect. time in response to exposure to THZ radiation. 0065. The terms “treating”, “treat” and “treatment” 0.058 As used herein, THZ radiation is refers to electro include (i) preventing a disease, pathologic or medical con magnetic waves having band frequencies of 0.1 terahertz to 3 dition from occurring (e.g., prophylaxis); (ii) inhibiting the terahertz. disease, pathologic or medical condition or arresting its 0059 References in the specification to “one embodi development; (iii) relieving the disease, pathologic or medi ment”, “an embodiment', etc., indicate that the embodiment cal condition; and/or (iv) diminishing symptoms associated described may include a particular aspect, feature, structure, with the disease, pathologic or medical condition. Thus, the moiety, or characteristic, but not every embodiment necessar terms “treat”, “treatment, and “treating can extend to pro ily includes that aspect, feature, structure, moiety, or charac phylaxis and can include prevent, prevention, preventing, teristic. Moreover, Such phrases may, but do not necessarily, lowering, stopping or reversing the progression or severity of refer to the same embodiment referred to in other portions of the condition or symptoms being treated. As such, the term the specification. Further, when a particular aspect, feature, “treatment' can include medical, therapeutic, and/or prophy structure, moiety, or characteristic is described in connection lactic administration, as appropriate. with an embodiment, it is within the knowledge of one skilled 0066. As will be understood by one skilled in the art, for in the art to affect or connect such aspect, feature, structure, any and all purposes, particularly in terms of providing a moiety, or characteristic with other embodiments, whether or written description, all ranges recited herein also encompass not explicitly described. any and all possible Sub-ranges and combinations of Sub 0060. The singular forms “a,” “an and “the include plu ranges thereof, as well as the individual values making up the ral reference unless the context clearly dictates otherwise. range, particularly integer values. A recited range (e.g., Thus, for example, a reference to “a compound includes a weight percentages or carbon groups) includes each specific plurality of Such compounds, so that a compound X includes value, integer, decimal, or identity within the range. Any a plurality of compounds X. It is further noted that the claims listed range can be easily recognized as sufficiently describ may be drafted to exclude any optional element. As such, this ing and enabling the same range being broken down into at statement is intended to serve as antecedent basis for the use least equal halves, thirds, quarters, fifths, or tenths. As a of exclusive terminology, such as “solely.” “only, and the non-limiting example, each range discussed herein can be like, in connection with any element described herein, and/or readily broken down into a lower third, middle third and the recitation of claim elements or use of “negative' limita upper third, etc. As will also be understood by one skilled in tions. the art, all language Such as “up to”, “at least”, “greater than'. 0061 The term “and/or means any one of the items, any “less than”, “more than', 'or more', and the like, include the combination of the items, or all of the items with which this number recited and Such terms refer to ranges that can be term is associated. The phrase “one or more' is readily under Subsequently broken down into Sub-ranges as discussed stood by one of skill in the art, particularly when read in above. In the same manner, all ratios recited herein also context of its usage. For example, one or more peptides of a include all sub-ratios falling within the broader ratio. Accord protein refers to one to five, or one to four, for example if the ingly, specific values recited for radicals, Substituents, and protein is fragmented. ranges, are for illustration only; they do not exclude other 0062. As used herein, the term “about” refers to an defined values or other values within defined ranges for radi approximately +/-10% variation from a given value. It is to be cals, claim elements, and the like. understood that Such a variation is always included in any 0067. One skilled in the art will also readily recognize that given value provided herein, whether or not it is specifically where members are grouped together in a common manner, referred to. Such as in a Markush group, the invention encompasses not 0063 As will be understood by the skilled artisan, all only the entire group listed as a whole, but each member of the numbers, including those expressing quantities of ingredi group individually and all possible Subgroups of the main ents, properties such as molecular weight, reaction condi group. Additionally, for all purposes, the invention encom tions, and so forth, are approximations and are understood as passes not only the main group, but also the main group being optionally modified in all instances by the term “about.” absent one or more of the group members. The invention These values can vary depending upon the desired properties therefore envisages the explicit exclusion of any one or more sought by those skilled in the art utilizing the teachings of the of members of a recited group. Accordingly, provisos may descriptions herein. It is also understood that such values apply to any of the disclosed categories or embodiments inherently contain variability necessarily resulting from the whereby any one or more of the recited elements, species, or standard deviations found in their respective testing measure embodiments, may be excluded from Such categories or mentS. embodiments, for example, for use in an explicit negative 0064. An “effective amount” refers to an amount effective limitation. to treat a disease, disorder, and/or condition, or to bring about 0068. The following Examples are intended to illustrate a recited effect. For example, an effective amount can be an the above invention and should not be construed as to narrow amount effective to reduce the progression or severity of the its scope. One skilled in the art will readily recognize that the condition or symptoms being treated. Determination of a Examples Suggest many other ways in which the invention therapeutically effective amount is well within the capacity of could be practiced. It should be understood that numerous US 2015/0217131 A1 Aug. 6, 2015

variations and modifications may be made while remaining of the tissues (as illustrated schematically by a dashed circle within the scope of the invention. in FIG. 1d) was analyzed using an Illumina Human HT-12 v4 Expression BeadChip 30 minutes after irradiation. EXAMPLES (0073. We found that intense THz pulses profoundly affect gene expression in directly exposed human skin. Exposure to Example 1 THZ pulses with an energy of 1.0LJ for 10 minutes altered the levels of 442 genes (FIG. 4), while irradiation by pulses with 0069. Recently, we demonstrated that intense, picosecond 10 times lower energy (0.1 LJ) for the same time duration THZ pulses significantly induce phosphorylation of H2AX in affected the expression of 397 genes as compared to unex human skin tissue, indicative of DNA damage. We also posed controls (FIG. 5). Interestingly, exposure to UVA observed THz-pulse-induced increases in the levels of mul pulses caused changes in the expression of only 290 genes tiple cell cycle regulatory and tumor suppressor proteins, (FIG. 6). The observed changes in gene expression profile Such as p53, p21, p16, Ku70, and EGR1, Suggesting that were not caused by THz-induced tissue heating. THZ expo cellular DNA repair machinery is activated in response to sures were carried out at ambient temperature (21°C.), and THz-pulse-induced DNA damage. Furthermore, recent the time-averaged power (1 mW) was low. Applying a theo experiments have demonstrated that exposure to broadband, retical formalism developed in ref 20, we estimate that the picosecond-duration THZ pulses results in gene expression temperature increase due to THZ exposure was less than 0.7° changes that depend on the type of exposed cells or tissues C. Furthermore, none of the heat shock protein encoding and are non-thermal in nature. For example, broadband, pico genes were differentially expressed in THz- or UVA-exposed second-duration THZ pulses influenced differentiation of tissues. mammalian stem cells and elicited parameter-specific 0074 Analysis of the overlaps in the lists of genes differ changes in the expression levels of genes that were transcrip entially expressed upon exposure to intense pulsed THZ and tionally active at a given differentiation time point. In human UV radiation revealed interesting trends (FIG.2). While there skin tissue, it was observed that intense THz pulses caused is a significant overlap between genes affected by both THz changes in expression levels of several cancer-related genes. pulse energies, little overlap exists between THz- and UVA 0070 Since the penetration of THz radiation into the induced gene expression profiles, which is not surprising human body is limited to the Sub-mm range, its effects on skin since there is a fundamental difference in how low photon tissue are most relevant for potential clinical applications. In energy (~4 meV), non-ionizing THZ radiation and high pho our preliminary study of the effects of intense THz pulses on ton energy (3.1 eV) UVA radiation interact with living cells. human skin tissue, we analyzed gene expression in the dis 0075 Differentially-expressed genes that were common sected portions of the tissue containing both directly exposed for both THZ pulse exposure regimes are of particular interest as well as neighboring unexposed portions, and noted as potential THz-pulse-exposure biomarkers that hold the key changes in gene expression. Yet, it is important to precisely to understanding cellular effects of intense THz pulses. We delineate the changes that occur exclusively in THZ-exposed identified 219 such genes, of which 164 are down-regulated tissue. Here we report on the impact of intense THz pulses on and 55 are up-regulated as a result of THZ pulse exposure. the global gene expression profile in human skin tissue. We Among them are genes involved in molecular etiology of find that exposure to intense THz pulses results in coordinated dermatological diseases (psoriasis, atopic dermatitis, epider changes in expression of multiple genes involved in epider mal hyperplasia, and dermatitis), cancer, and genes with mal differentiation. Many of the affected genes are implicated important functions in apoptotic signaling pathways. in inflammatory skin diseases such as psoriasis and atopic 0076 We also find that the affected genes are not uni dermatitis and in non-melanoma skin cancer, Suggesting the formly distributed throughout the genome. The most striking possibility for novel treatment modalities based on intense changes were observed in the expression of epidermal differ THZ pulses. entiation complex (EDC) genes. EDC describes the 1.6-Mb on human chromosome 1 q21 that contains 57 genes Results encoding S100 proteins as well as structural proteins of epi 0071. We have exposed artificial human skin tissues to dermal cornification (FIG. 3a). Of them, 16 were markedly picosecond-duration (FIG.1a) broadband (0.2-2.5THZ, FIG. down-regulated by exposure to intense THz pulses in both 1b) THz pulses with 1 kHz repetition rate, 1/e spot-size intensity regimes, compared to only 5 affected by UVA pulses diameter of 1.5 mm (FIG.1c) and pulse energies of either 1.0 (FIG. 3b). THz-pulse-affected genes include members of the LJ or 0.1 L.J. For comparison, we have exposed skin tissues to Small Proline Rich Region (SPRR), involucrin (IVL), Late UVA pulses (400 nm, 0.1 ps, 0.024 LJ). While DNA does not Cornified Envelope (LCE) and the S100 families, as well as directly absorb UVA, its cytotoxicity and genotoxicity are NICE-1 and comulin (CRNN). In addition to EDC genes, mediated by the generation of reactive oxygen species that in exposure to intense THz pulses also altered expression levels turn damage DNA and other cellular components. of many other genes implicated in cancer and dermatological 0072 The full thickness human normal skin tissue used, diseases (FIG.3e). EpiDermFT, is a multilayered, highly differentiated model of dermis and epidermis (FIG. 1d). It is mitotically and meta Discussion. bolically active, preserves the arrangement and communica 0077 EDC complex genes are responsible for terminal tion of cells present in tissues in Vivo, and thus provides an differentiation of keratinocytes and regulation of epidermal excellent platform for assessing the effects of exposure to barrier function, as well as for skin immune and inflammation intense THZ pulses. Tissue samples were placed at the focus responses, Up-regulation of EDC genes leads to increased of the pulsed THZ beam for 10 minutes (FIG. 1e) or at the proliferation and differentiation of keratinocytes commonly focus of the pulsed 400 nm beam for two minutes. Global observed in inflammatory skin disorders such as psoriasis and gene expression in excised 2 mm-diameter exposed portions atopic dermatitis, as well as in skin cancers. The 1q21 locus US 2015/0217131 A1 Aug. 6, 2015 has been identified as one of the key psoriasis susceptibility amplify existing (or create new) open states in the double loci (PSORS4) in clinical genome-wide linkage studies. Of helix, thereby affecting transcription initiation or binding of the EDC genes that were down-regulated by intense THz transcription factors. Alternatively, the changes in gene pulses (FIG. 3b), many, including S100A15, S100A12, expression may constitute a cellular response to intense-THZ SPRR2A, SPRR3, SPRR2B, LCE3 genes, are up-regulated in pulse-induced damage to DNA or intracellular proteins, psoriasis. which initiates multiple cellular-damage-repair pathways. In 0078 Enhanced expression of multiple EDC genes, the future, a detailed analysis of the impact of intense THz including members of the SPRR family, S100 genes that pulses on the activity of various transcription factors common encode for calcium-binding proteins, and multiple cornified to affected genes is needed to elucidate the exact cellular and envelope genes, has been identified as a hallmark of cutane molecular effects of intense THz pulses. ous squamous cell carcinomas (SCC). Of these SCC-associ I0082. Additionally, analysis of transcriptional changes ated EDC genes, eight, including S100A11, S100A12, seen in skin tissue that is directly exposed to intense THz SPRR1B, SPRR2B, SPRR2C, SPRR3, involucrin (IVL), and radiation and in the mixture of directly exposed and neigh LCE3D, are down-regulated by intense THz pulse exposure boring naive tissue' indicates that exposure to intense THz (FIG. 3b). Down regulation of these genes by intense THz pulses can induce out-of-field bystander effects. While pulses may open new avenues for targeted treatments for bystander effects are accepted to occur after exposure to psoriasis and SCC. ionizing radiation, the existence, extent and mechanisms of 0079 Besides EDC genes, THZ pulses affected numerous THz-pulse-induced bystander effects need to be further ana other genes involved in psoriasis, atopic dermatitis and other lyzed. inflammatory skin diseases, as well as in many cancer types, I0083. While a number of earlier studies investigated the Such as aggressive oral squamous cell carcinoma (OSCC) and biological effects of continuous-wave THz radiation and non-melanoma skin cancer (SCC and basal cell carcinoma found that the majority of the observed effects are thermal in (BCC)) (FIG.3c). We observe down regulation of corneodes nature, the present study is one of the very few to date that mosin (CDSN), a member of the PSORS1 psoriasis suscep have explored genotoxic, cytotoxic and epigenetic effects of tibility locus, and CD24, a key pro-inflammatory gene, both picosecond and subpicosecond broadband THZ pulses. The of which are usually over-expressed in psoriatic skin. The low average power of THZ pulse sources results in biologi CD24 gene encodes for a mucin-like adhesion molecule, and cally insignificant temperature increases of only fractions of its over expression has been also repeatedly associated with a degree at most. However, the high energy density per pulse aggressive tumor progression, metastasis and poor prognosis produces peak powers and corresponding electric fields that in various cancers. It is also up-regulated in SCC. Addition can be extremely high. It is likely that these high peak electric ally, THZ exposure significantly lowered mRNA expression fields are responsible for the observed THz-pulse-driven cel of human B-defensins (DEFB103A, DEFB4, LOC728454, lular effects. and DEFB1). Interestingly, the impact of intense THz pulses I0084. In 2003, Clothier and Bourne reported that picosec on the expression levels of B-defensins was similar to that of ond-duration, 0.2-3.0 THz bandwidth THZ pulses had no UVA pulses. Enhanced expression of B-defensins is associ discernible effect on the differentiation, activity or viability of ated with non-melanoma skin cancer (basal cell carcinoma primary human keratinocytes in vitro. Based on the experi (BCC) and SCC), and OSCC, as well as psoriasis. mental details provided in the paper, we estimate that the 0080 Exposure to intense THz pulses also suppressed energy density perpulse was -3 p.J/cm (3x10/cm). In a levels of four serine proteinase inhibitor (serpin) B genes that recent work, Williams et al. explored the influence of more map to the serpin Superfamily locus at chromosome 1821.3, intense THz pulses produced by the ALICE (Daresbury Labo once again demonstrating a non-uniform distribution of ratory, UK) synchrotron Source, with energy densities per intense-THZ-pulse-affected genes throughout the genome. pulse reaching 10 nJ/cm (0.01 J/cm), on the attachment, Two of them, serpinB3 and serpinB4, are also known as morphology, proliferation and differentiation of human epi squamous cell carcinoma antigens 1 and 2, respectively. Their thelial and embryonic stem cells. Like Clothier and Bourne, elevated expression is associated with aggressive SCCs and they reported no changes in cell properties. psoriasis. SerpinB13, or hurpin, is also over-expressed in I0085. On the other hand, a series of experiments investi SCC, as well as in psoriatic lesions. Another down-regulated gating the effects of broadband (~1-15 THz, centered at 10 member of the serpin family is serpinB7, or megsin. Finally, THZ), Subpicosend THZ pulses on mouse mesenchymal stem intense THz pulses (but not UVA pulses) down-regulated the cells (Bock et al., Alexandrov et al.) revealed THz-induced S100P gene that is related in function to the S100A family of changes in the expression of the genes transcriptionally active genes of EDC and encodes for a member of the Ca"-binding at a given differentiation stage of stem cells. Furthermore, the proteins family. Over-expression of S100P has been shown to same studies found that THZ pulse exposure accelerated cell act as a proliferative and anti-apoptotic factor in many tumor differentiation toward adipose phenotype. In these experi types. Moreover, targeted disruption of S100P was recently ments, the energy density perpulse was significantly higher at shown to Suppress the growth of hepatocellular carcinoma 1 J/cm, which may suggest the existence of a THz pulse cells. While the exact role of serpins as well as S100P in skin energy density (and corresponding peak THZ electric field) cancer and inflammatory skin diseases is yet to be elucidated, threshold for the induction of changes in cellular function. their concerted down-regulation by intense THZ pulses might Finally, in our work, the energy density per pulse was ~6 have clinical relevance and should therefore be further inves J/cm for 0.1 JTHz pulses and ~60 J/cm for 1 JTHz tigated. pulses, resulting in specific gene expression changes in 0081 Furthermore, the mechanisms by which intense human skin tissue. Clearly, more extensive studies are needed THZ pulses influence gene expression are not yet known. to determine pulse energy density thresholds and other expo Based on mesoscopic modelling of DNA breathing dynamics Sure parameters for the onset of THZ-pulse-induced changes in a THz field, it has been suggested that THZ radiation may to gene expression and cellular function. 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I0086. In summary, we have shown that intense THz pulses 0091 Four tissue samples were used for each of the four have profound impact on global gene expression in human experimental conditions (control, 1.0 THZ and 0.1 LJ THz skin. Furthermore, we observed that the distribution of pulses, and UVA). Following exposure, the tissues were incu intense-THZ-pulse-sensitive genes is not uniform across the bated at 37°C. in 5% CO, atmosphere for 30 minutes in a genome, with a significant number of affected genes belong multiwell dish filled with fresh medium, followed by a snap ing to the epidermal differentiation complex in the 1 q21 freeze in liquid nitrogen. Control tissues underwent the same locus. Finally, the observed THz-induced changes in expres procedure other than being irradiated. The central region (2 sion of EDC genes and other genes implicated in non-mela mm in diameter, as shown in FIG. 1c) containing the exposed noma skin cancers and inflammatory skin disorders such as portion of the frozen tissues was cut out and used for gene psoriasis, Suggests the potential application of intense THz expression analysis. pulses for treatment aimed at normalizing the expression of these disease-related genes. Picosecond duration, intense Whole-Genome Gene Expression Profiling. THZ pulses are non-ionizing, do not cause tissue overheating 0092 RNA. Isolation. and can be focused with ~1 mm precision for delivering safe, (0093 Total RNA was isolated using the Illustra RNAspin non-invasive treatment. Of course, since the present study mini kit (GE Healthcare Life Sciences, Buckinghamshire, concentrated on analyzing changes in gene expression in UK) were processed following the manufacturers instruc human skin tissue 30 minutes after 10-minute-long exposure tions. Samples were eluted in Ultrapure DNase/RNase-free to intense THZ pulses, it essentially provides a Snapshot of distilled water, which was provided in the kit. RNA samples THz-pulse-induced effects. Extensive studies tracking the were quantified using ultraviolet spectroscopy (NanoDrop, THZ-induced-changes in gene expression and the resulting Wilmington, Del.) and were further assessed for RNA integ changes in protein expression over a period of time following rity (RIN) on the Agilent 2100 Bioanalyzer (Santa Clara, the exposure of healthy as well as diseased tissues will have to Calif.) using the RNA Nano-chip Kit. RNA samples with RIN be carried out to assess the full potential of intense THz pulses values of seven or better were used for the further analysis. for therapeutic applications. We envision the study presented (0094 Library Preparation. here as an essential roadmap for this future work. 0.095 CRNA was created using the Ambion's Illumina Materials and Methods. TotalPrep RNA Amplification Kit (Applied Biosystems, Carlsbad, Calif.) with an input of 400 ng of total RNA per 0087 Generation and Characterization of Intense THz sample. Briefly, oligo-dT primers were used to synthesize Pulses. first strand cDNA containing a phage T7 promoter sequence. 0088 We have exposed human skin tissues to THZ pulses Single-stranded cDNA was converted into a double-stranded with 1 kHz repetition rate and pulse energies of either 1.0LJ DNA template via DNA polymerase. RNase H simulta or 0.1 L.J. The THz pulses were generated by optical rectifi neously acted to degrade the RNA. Samples of cDNA were cation of tilted-pulse-front 800 nm pulses from an amplified purified in filter cartridges to remove excess RNA, primers, Ti:sapphire laser source in a LiNbO, crystal. A black poly enzymes and salts. The recovered cDNA was subjected to in ethylene sheet placed after the LiNbO crystal filtered out the vitro transcription using biotinylated UTPs. This step created, remaining 800 nm beam while letting the THz pulses through labeled and amplified cRNA. A final purification step with minimal attenuation. The energy of the THz pulses was removed unincorporated NTPs, salts, inorganic phosphates monitored by a pyroelectric detector (Spectrum Detector, and enzymes, which prepared the samples for hybridization. Inc.) with an active area of 6x7 mm. Wire grid polarizers (0096 Hybridization and Detection. were used to attenuate the THz pulse energy. The THz pulse 0097 Illumina’s direct hybridization assay kit was used to waveform (FIG. 1a) was measured by electro-optic sampling process samples according to the manufacturer's protocol in 0.5 mm-thick 110 ZnTe crystal. The THz spot size at the (Illumina, San Diego, Calif.). Overnight, 750 ng from each focus was determined by imaging the THZ beam on a pyro cRNA sample was hybridized into the Illumina HumanHT electric infrared camera. The peak electric field was calcu 12 V4 Whole Genome Expression BeadChip arrays. After lated as discussed. The peak THz electric field was 220 ward, a 10-min incubation with a supplied wash buffer at 55° kV/cm for 1.0LJ and 70 kV/cm for 0.1 LJ energy THZ pulses. C. preceded a 5-min room temperature (~22°C.) wash. The Exposure to 400 nm pulses for two minutes was also used. arrays were incubated in 100% ethanol for 10 min. A second The UVA pulses were generated by second harmonic genera room temperature wash lasted 2 min with gentle shaking, tion in a BBO crystal. A shortpass filter placed after the BBO which completed this high Stringency wash step. The arrays crystal blocked any remaining 800 nm beam. The UVA spot were blocked with a buffer for 10 min and washed before a size at the tissue Surface was 2.7 mm diameter. 10-min steptavidin-Cy3 (1:1,000) probing. After a 5-min I0089 Tissue Models and Handling. wash at room temperature, the BeadChips were dried and 0090 We used the in vivo full thickness artificial human imaged. Six controls were also built into the Whole-Genome skin tissues model, EpiDermFT by Mattek, to study the Gene Expression Direct Hybridization Assay system to cover effects of intense THz pulses on gene expression. EpiDermET aspects of the array experiments, including controls for: the recreates normal skin tissue structure with differentiated der biological specimen (14 probes for housekeeping controls), 3 mis and epidermis. It consists of human-derived epidermal controls for hybridization (6 probes for Cy3-labeled hybrid keratinocytes and dermal fibroblasts that are mitotically and ization, 4 probes for low Stringency hybridization, and 1 metabolically active. The tissues were cultured according to probe for high Stringency hybridization), signal generation (2 the manufacturer's protocol, using an air-liquid interface tis probes for biotin control), and approximately 800 probes for Sue culture technique. Unexposed tissue samples served as negative controls on an 8-sample BeadChip. The arrays were controls. Skin tissues in single well plate inserts were placed scanned on the iScan platform (Illumina), and data were at the focus of the THz beam for 10 minutes, or at the focus of normalized and scrutinized using Illumina BeadStudio Soft the UVA beam for 2 minutes. Wa. US 2015/0217131 A1 Aug. 6, 2015

0098 BeadChip Statistical Analysis and Data Processing. 9. The method of claim 1 wherein the pulses of terahertz 0099. The false discovery rate (FDR) was controlled using radiation have a repetition rate of about 1 hertz to about 100 the Benjamini-Hochberg method. The Illumina Custom megahertz. Model took the FDR into account and was used to analyze the 10. The method of claim 9 wherein the pulses of terahertz data. Differential gene expression (at least a 2-fold change) radiation have a repetition rate of about 1 kilohertz. from sham-treated tissues was determined to be statistically 11. The method of claim 1 wherein the modulation of gene significant if the p value after the Benjamini-Hochberg expression is a down-regulation of gene expression. 12. The method of claim 1 wherein the modulation of gene method adjustment was lower than 0.05. The values were expression is an up-regulation of gene expression. transformed to show a log 2 scale. Lists of regulated tran 13. The method of claim 1 wherein the disease state is skin scripts were inserted into the web based DAVID Bioinformat CaCC. ics Resources 6.7 (NIAID/NIH) Functional Annotation Tool. 14. The method of claim 13 wherein the skin cancer is 0100. Accession Numbers. non-melanoma skin cancer. 0101 The raw and processed gene expression data for this 15. The method of claim 14 wherein the non-melanoma project have been deposited in the Gene Expression Omnibus skin cancer is a squamous cell carcinoma or basal cell carci (GEO) database, www.ncbi.nlm.nih.gov/geo (GSE48586). Oa. What is claimed is: 16. The method of claim 1 wherein the disease state is an 1. A method for treating a disease state in skin cells or skin inflammatory skin disease. tissue using terahertz radiation, the method comprising the 17. The method of claim 14 wherein the disease state is steps of: psoriasis or atopic dermatitis. 18. The method of claim 11 wherein at least one of the a) providing a source of terahertz radiation; and genes down-regulated is selected from the group consisting of b) exposing the skin cells or skin tissue to pulses of tera S100P, S100A11, S100A12, S100A15, SPRR2A, SPRR3, hertz radiation in an effective amount to induce modu SPRR1B, SPRR2B, SPRR2C, LCE3, LCE3D, CD24, lation of gene expression in the skin cells or skin tissue; DEFB103A, DEFB4, LOC728454, DEFB1, IVL SER wherein the modulation of gene expression results in a reduc PINB3, SERPINB4 and SERPINB13. tion of the disease state in the skin cells or skin tissue. 19. The method of claim 12 wherein at least one of the 2. The method of claim 1 wherein the terahertz radiation genes up-regulated is selected from the group consisting of has a bandwidth of about 0.1 to about 10 terahertz. LCE1A, LCE1B, LCE1C, LCE1D, LCE1 E, LCE1F and 3. The method of claim 2 wherein the terahertz radiation LCE5A. has a bandwidth of about 0.2-2.5 terahertz. 20. A method for treating a patient with skin cancer using 4. The method of claim 1 wherein the pulse of terahertz terahertz radiation, the method comprising the steps of radiation is about 0.2 picoseconds to about 100 picoseconds a) providing a source of terahertz radiation; and in duration. b) exposing the patient to pulses of terahertz radiation, 5. The method of claim 4 wherein the pulse of terahertz wherein the pulses of terahertz radiation have a band radiation is about 10 picoseconds in duration. width of about 0.2-2.5 terahertz, a pulse energy of about 6. The method of claim 1 wherein the duration of exposure 0.1-1.0 microjoules for about 30 minutes: to terahertz radiation is about 1 minute to about 30 minutes. wherein the exposure to the terahertz radiation is an effec 7. The method of claim 1 wherein the pulses of terahertz tive amount to induce at least a 1.5 fold change in gene radiation have a pulse energy of about 0.01 microjoules to expression in the skin cancer cells as compared to a about 100 microjoules. control sample not exposed to terahertz radiation; and 8. The method of claim 7 wherein the pulses of terahertz wherein the change in gene expression results in a reduc radiation have a pulse energy of about 0.1 microjoules to tion in the level of skin cancer in the patient. about 2.0 microjoules. k k k k k