Hidradenitis Suppurativa and Comorbid Disorder Biomarkers, Druggable Genes, New Drugs and Drug Repurposing—A Molecular Meta-Analysis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Literature Search
2.2. Study Selection
2.3. Data Extraction
2.4. Data Analysis
2.5. Drug Repurposing Sources
2.6. Statistics
3. Results
3.1. Study Selection Process
3.2. Differentially Expressed Genes and Proteins in HS
3.3. HS Biomarkers
3.4. Enrichment Analysis of HS-Associated Genes
3.5. Enrichment Analysis of HS Druggable Genes
3.6. Study Drugs and Drug Repurposing for HS
4. Discussion
4.1. HS Pathogenesis
4.2. HS Comorbid Disorders
4.3. Study Drugs and Drug Repurposing for HS
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Blood | Skin | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Gene | +/− | mRNA | Protein | +/− | mRNA | Protein | Name | Other skin disorders | HS comorbid disorders | Drugs |
ADAM12 | + | [3,27] | ADAM Metallopeptidase Domain 12 | Down syndrome | ||||||
ADIPOQ | − | [28] | − | [27] | Adiponectin | Glucose intolerance, metabolic syndrome | Piogitazone | |||
AR | + | [3,33,34] | [35] | Androgen receptor | Polycystic ovary syndrome, alopecia | Androgen insensitivity syndrome | Cyproterone acetate, Flutamide, Nilutamide, Bicalutamide, 17α-Propionate, AZD3514 | |||
BTK | +/(−) | [3,27,33,34] | Betacellulin | Squamous cell carcinoma | Cetuximab | |||||
C3 | − | [27] | + | [30] | Complement C3 | Zinc, Zinc acetate | ||||
C5AR1 | + | [3,30] | Complement C5a Receptor 1 | Hypersensitivity reaction type III disease | Compstatin, PMX 205, PMX 53, W 54011 | |||||
CASP1 | + | [38,39] | Caspase 1 | Schnitzler syndrome | Familial Mediterranean fever | Minocyclin | ||||
CCL18 | + | [27,30] | [43] | C-C Motif Chemokine Ligand 18 | Eczema | |||||
CCL26 | + | [41] | + | [30] | C-C Motif Chemokine Ligand 26 | |||||
CCR4 | + | [45] | + | [30,45] | C-C Motif Chemokine Receptor 4 | Mycosis fungoides, cutaneous T cell lymphoma, allergic contact dermatitis | ||||
CD80 | + | [30,38] | CD80 Molecule | Abatacept, Belatacept | ||||||
CHI3L1 | + | [49] | + | [50] | Chitinase 3-Like 1 | Erysipelas | ||||
CSF1 | + | [3,33,34,40] | Colony-Stimulating Factor 1 | Rheumatoid arthritis | ||||||
CXCL1 | + | [27,40,42,44,45] | [40] | C-X-C Motif Chemokine Ligand 1 | Kaposi sarcoma | Formic acid | ||||
CXCL8 | + | [30,42,44] | [41] | C-X-C Motif Chemokine Ligand 8 | Melanoma | Simvastatin | ||||
CXCL10 | − | [41] | + | [30] | [41] | C-X-C Motif Chemokine Ligand 10 | Eldelumab | |||
CXCL13 | + | [30,42,45] | [26] | C-X-C Motif Chemokine Ligand 13 | T cell lymphoma | |||||
CXCR5 | + | [30] | [26] | C-X-C Motif Chemokine Receptor 5 | T cell lymphoma | |||||
DCD | − | [27,32,33] | [32] | Dermcidin | Netherton syndrome, tinea pedis | Basiliximab, Zinc sulfate | ||||
DEFB4A | +/(−) | [3,27,30,32,39,44,45,46] | [3,53] | Defensin β 4A | Tinea corporis, oral candidiasis | |||||
DEFB103B | + | [46,52] | Defensin β 103B | |||||||
EGF | + | [3,33,34] | Epidermal Growth Factor | Cetuximab, AG 490, CGP 52411, Genistein, Zanubrutinib (receptor antagonist) | ||||||
EPGN | + | [3,33,34] | Epithelial Mitogen | Seborrheic dermatitis | ||||||
ERBB4 | − | [27,32] | Erb-B2 Receptor Tyrosine Kinase 4 | Gefitinib, Afatinib, Fostamatinib, AG 490, CGP 52411, Genistein | ||||||
EREG | + | [3,33,34] | Epiregulin | |||||||
GAS6 | +/(−) | [3,33,34] | Growth Arrest Specific 6 | Lupus erythematosus | ||||||
GDNF | + | [3,33,34] | [36] | Glial Cell Derived Neurotrophic Factor | Chondroitin sulphate | |||||
GJB2 | + | [3] | [3] | Gap Junction Protein β2 | Keratitis-Ichthyosis-Deafness Syndrome | Carbenoxolone disodium | ||||
HBEGF | + | [3,33,34] | Heparin Binding EGF-Like Growth Factor | |||||||
HGF | + | [3,33,34] | Hepatocyte Growth Factor | Dexamethasone, Neratinib, Erlotinib | ||||||
HRG | + | [3,33,34] | Histidine-Rich Glycoprotein | Zinc sulfate | ||||||
IFNA1 | + | [3,26,30,33,34] | Interferon α1 | Cryoblobulinemia | ||||||
IFNG | + | [3,26,30,33,34,40,44,45,46] | Interferon γ | Oksalazine, Emapalumab, Glucosamine | ||||||
IGF2 | + | [3,33,34] | Insulin-Like Growth Factor 2 | |||||||
IGHD | + | [27,30] | Immunoglobulin Heavy Constant δ | |||||||
IGHG3 | + | [27,30] | Immunoglobulin Heavy Constant γ3 (G3m Marker) | |||||||
IGKV1D-13 | + | [27,30] | Immunoglobulin κ Variable 1D-13 | |||||||
IGLV | + | [27,30] | Immunoglobulin λ Variable Cluster | |||||||
IL1A | + | [3,26,30,33,34,40] | [39] | Interleukin 1α | Acne, Irritant dermatitis | Arthritis | Anakinra, Rinolacept, Olanzapine, Pirfenidone, Thalidomide, AMG-108 | |||
IL1B | + | [26,30,38,40,42,46] | [38,56] | Interleukin 1β | Gingivitis, Muckle–Wells syndrome, Toxic shock syndrome | Canakizumab, Anakinra (receptor antagonist), Rinolacept (receptor antagonist), Minocycline | ||||
IL2 | + | [26,30] | Interleukin 2 | Graft-versus-host disease, Leprosy | Suplatast tosylate, Daclizumab (receptor antagonist), Basiliximab (receptor antagonist), Rituxomab, Thalidomide, Cafazolin | |||||
IL2RA | + | [49,56] | + | [30] | Interleukin 2 Receptor Subunit α | Type 1 diabetes mellitus, Juvenile arthritis | Daclizumab, Basiliximab, Pirfenidone, Thalidomide | |||
IL4 | + | [3,30,33,34,40] | Interleukin 4 | Atopy, Allergic rhinitis, Food allergy | Dupilumab (receptor antagonist), Calcitriol | |||||
IL6 | + | [40] | + | [3,26,30,33,34,40,42] | [40,58] | Interleukin 6 | Siltuximab, Tocilizumab (receptor antagonist), Sarilumab (receptor antagonist), Satralizumab (receptor antagonist), Vitamin C, Vitamin E | |||
IL10 | + | [30,38,44,46] | [52,56] | Interleukin 10 | Nicotinamide, Niacin, Cyclosporine A, Methotrexate, Mycofenolate mofetil | |||||
IL12A | + | [59] | [41] | Interleukin 12A | Adamantiades–Behçet’s disease | Primary biliary cholangiitis | Mycophenolate mofetil, Ustekinumab (IL-12/23), Briakinumab (IL-12/23) | |||
IL12B | + | [30] | [36] | Interleukin 12B | Psoriasis | Ustekinumab (IL-12/23), Briakinumab (IL-12/23) | ||||
IL13 | +/(−) | [3,30,45] | Interleukin 13 | Allergic rhinitis, Penicillin allergy | Suplatast tosylate, Montelukast, Omalizumab | |||||
IL16 | + | [30] | [41] | Interleukin 16 | Allergic asthma | |||||
IL17A | + | [59] | + | [3,30,33,34,38,39,40,42,44,46,60] | [4,36,38,39,41] | Interleukin 17A | Allergic contact dermatitis | Arthritis | Secukizumab, Ixekizumab, Bimekizumab (IL-17A/F), Brodalumab (receptor antagonist), Vidofludimus | |
IL17F | + | [30,39,40,42,45] | Interleukin 17F | Candidiasis, Acute generalized exanthematous pustulosis, Mail diseases | Bimekizumab (IL-17A/F), Brodaluman (receptor antagonist) | |||||
IL17R | + | [3] | [4] | Interleukin 17 Receptor | Candidiasis | Arthritis | Brodalumab | |||
IL18 | +/− | [26,30] | [38] | Interleukin 18 | IAP antagonist, Iboctadekin + Doxil | |||||
IL19 | + | [3,30,40] | Interleukin 19 | Psoriasis | Inflammatory bowel disease, Arthritis | |||||
IL20 | +/− | [30,46] | [46] | Interleukin 20 | Psoriasis | |||||
IL21 | + | [30,39] | Interleukin 21 | Dacryoadenitis, Inflammatory boel disease | ||||||
IL22 | +/(−) | [3,30,40,42,46] | [46] | Interleukin 22 | Candidiasis | Inflammatory bowel disease | ||||
IL22RA1 | − | [30] | [46] | Interleukin 22 Receptor Subunit α1 | Spondyloarthropathy, rheumatoid arthritis, autoimmune uveitis | |||||
IL23A | + | [30,40,61] | Interleukin 23 Subunit α | Autoimmune disease | Inflammatory bowel disease, Arthritis | Guselkumab, Risankinumab, Tildrakizumab, Ustekinumab (IL-12/23), Briakinumab (IL-12/23) | ||||
IL24 | + | [30,42,46] | Interleukin 24 | Melanoma, chronic spontaneous urticaria, psoriasis | Spondylarthropathy | |||||
IL26 | + | [42,46] | Interleukin 26 | Psoriasis | Inflammatory bowel disease, Crohn’s disease | |||||
IL32 | + | [30,40,61] | Interleukin 32 | Cutaneous diphtheria | ||||||
IL36A | + | [62] | + | [30,40,42,45,61] | [39,61] | Interleukin 36α | Psoriasis | Spesolimab (receptor antagonist) | ||
IL36B | + | [62] | + | [61] | Interleukin 36β | Periostitis | Spesolimab (receptor antagonist) | |||
IL36G | + | [62] | + | [30,40,42,45] | [61] | Interleukin 36γ | Acute generalized exanthematous pustulosis, Psoriasis | Spesolimab (receptor antagonist) | ||
IL37 | − | [32,33,42] | Interleukin 37 | Still’s disease | Inflammatory bowel disease | Ustekinumab (IL-12/23) | ||||
JAK3 | + | [3,30] | Janus Kinase 3 | NK cell enteropathy | Decernatinib, Tofacitinib (JAK1/3), Ruxolitinib (JAK1/3), PF-06651600, AT-501, ATI-502, Cerdulatinib (JAK1/2/3, SYK), Delgocitinib (JAK1/2/3), Peficitinib (JAK1/2/3), Zanubrutinib (JAK3/ITR/EGFR), Cercosporamide JAK3/Mnk2) | |||||
KRT6A | + | [3,32] | [3] | Keratin 6A | Pachyonychia congenita, Lingua plicata, Cheilitis | Zinc, Zinc acetate | ||||
KRT16 | + | [3,27,30,32] | [3] | Keratin 16 | Pachyonychia congenita, palmoplantar keratoderma | |||||
KRT77 | − | [27,32,33] | [32] | Keratin 77 | Epidermolytic palmoplantar keratoderma, Buschke-Ollendorff syndrome | |||||
LCE3D | + | [32] | [32] | Late Cornified Envelope 3D | Psoriasis | |||||
LGR5 | − | [27,32] | Leucine Rich Repeat Containing G Protein-Coupled Receptor 5 | Type II diabetes mellitus | ||||||
LTA4H | − | [27,65] | + | [31] | Leukotriene A4 Hydrolase | Captopril, Dexamethasone, Montelukast | ||||
MMP1 | + | [3,30] | [3] | Matrix Metallopeptidase 1 | Epidermolysis bullosa atrophica, Scleroderma | Zinc, Collagenase | ||||
MMP3 | + | [40] | [40] | Matrix Metallopeptidase 3 | Coronary heart disease, Arthritis | Pravastatin, Simvastatin, Prothalidone, Lisinopril | ||||
MMP9 | + | [3,30,40] | [3] | Matrix Metallopeptidase 9 | Minocycline, Capropril, Simvastatin, Zinc, Zinc acetate | |||||
MMP12 | + | [27,30] | Matrix Metallopeptidase 12 | Dermatitis herpetiformis, Middermal elastolysis | Arthritis | Acetohydroxamic acid, Batimastat | ||||
NAMPT | + | [28,63] | Nicotinamide Phosphoribosyl transferase | Skin aging, pellagra, diabetes mellitus type 2, polycystic ovary syndrome | Nicotinamide, Niacin | |||||
NGF | + | [3,33,34] | [36] | Nerve Growth Factor | Clenbuterol | |||||
OSM | + | [3,26] | [36] | Oncostatin M | Kaposi sarcoma | |||||
PI3 | + | [3,27,32,33] | [3] | Peptidase Inhibitor 3 | Pustular psoriasis, impetigo herpetiformis, erysipelas | |||||
PIP | − | [27,32] | Prolactin Induced Protein | |||||||
PLIN1 | +/− | [27,48] | Perilipin 1 | Rosiglitazone | ||||||
S100A7 | + | [3,30,33,39,42,44,46] | [32] | S100 Calcium-Binding Protein A7 | Psoriasis, Squamous cell carcinoma | Anal fistula | Ibuprofen, Dexibuprofen, Zinc, Zinc acetate, Zinc chloride | |||
S100A7A | + | [3,27,32] | [3,32] | S100 Calcium-Binding Protein A7A | Psoriasis | |||||
S100A8 | + | [57] | + | [3,33,34,44] | [3,32] | S100 Calcium-Binding Protein A8 | Zinc, Zinc acetate, Zinc chloride, Copper | |||
S100A9 | + | [57] | + | [3,27,32,33,42,44,46] | [3,32] | S100 Calcium-Binding Protein A9 | Crohn’s disease, Rheumatoid arthritis | Zinc, Zinc acetate, Zinc chloride, Calcium | ||
S100A12 | + | [3,30,32,42] | [3,41] | S100 Calcium-Binding Protein A12 | Kawasaki disease | Psoriatic arthritis | Amlexanox, Olopatadine | |||
SCGB1D2 | − | [27,32] | Secretoglobin Family 1D Member 2 | |||||||
SCGB2A2 | − | [27,32,33] | Secretoglobin Family 2A Member 2 | |||||||
SERPINB3 | + | [3,27,30] | [3] | Serpin Family B Member 3 | Squamous cell caecinoma | Phosphoserine | ||||
SERPINB4 | + | [3,27,30] | [3] | Serpin Family B Member 4 | Squamous cell carcinoma | |||||
SLAMF7 | + | [3,27] | SLAM Family Member 7 | IgG4-related disease | Elotuzumab | |||||
SPRR2B | + | [32] | [32] | Small Proline Rich Protein 2B | Photosensitive trichothio-dystrophy 1, Autosomal reces-sive congenital ichthyosis | |||||
SPRR2C (pseudogene) | + | [32] | [32] | Small Proline Rich Protein 2C (Pseudogene) | ||||||
SPRR3 | + | [3] | [3] | Small Proline Rich Protein 3 | Genodermatoses | |||||
STAT1 | + | [3,26,30,44] | [36] | Signal Transducer and Activator of Transcription 1 | Methimazole, Niclosamide, Nifuroxazide, Sulforaphane | |||||
TCN1 | + | [3,27,45] | [3] | Transcobalamin 1 | Hydroxycobalamin, Cyanocobalamin, Cobalt | |||||
TLR2 | + | [3,68] | Toll-Like Receptor 2 | Leprosy, Borreliosis | Colorectal cancer | Adapalene, Cyproterone acetate | ||||
TLR4 | +/− | [26] | [53] | Toll-like Receptor 4 | Paclitaxel, Tacrolimus, Cyclobenzaprine | |||||
TMPRSS1D | + | [3] | [3] | Transmembrane Serine Protease 11D | ||||||
TNF | + | [3,26,30,32,33,38,40] | [56] | Tumor Necrosis Factor | Psoriasis, Toxic shock syndrome | Inflammatory bowel diseases, Arthritis | Adalimumab, Infliximab, Golimumab, Etanercept (receptor antagonist), Certolizumab pegol, Thalidomide, Lenalidomide, Pomalidomide, Calcitriol, Bay 11-7821, (R)-DOI, Cannabidiol | |||
TNFRSF4 | + | [45] | + | [45] | TNF Receptor Superfamily Member 4 | Kaposi sarcoma, Graft-versus-host disease, Drug reaction with eosinophilia | OX-40 ligand | |||
TNFSF11 | + | [30] | [36] | TNF Superfamily Member 11 | Letrozole, Thiocolchicoside | |||||
TNFSF13 (APRIL) | + | [30] | [26] | TNF Superfamily Member 13 | Autoimmune diseases | Rheumatoid arthritis | Pomalidomide, TACI-IG | |||
TNFSF13B (BAFF) | + | [30] | [26] | TNF Superfamily Member 13b | Autoimmune diseases, Sialadenitis, Sjogren syndrome | Belimumab, Blisibimod, LY2127399, TACI-IG | ||||
TNFSF14 | + | [30] | [36] | TNF Superfamily Member 14 | Herpes simplex | Rheumatoid arthritis | ||||
TNIP1 | +/− | [26,30] | TNFAIP3 Interacting Protein 1 | Systemic lupus erythematosus, Psoriatic arthritis | Rheumatoid arthritis, Arthritis | |||||
WIF1 | − | [27,32] | WNT Inhibitory Factor 1 |
Compound | Function | Gene Regulation | Development Phase |
---|---|---|---|
Probable repurposing HS drugs | |||
3,3’-Diindolylmethane | CHK inhibitor, cytochrome P450 activator, indoleamine 2,3-dioxygenase inhibitor | AR, HIF1A, IFNG, PI3 | 3 |
AG-490 | EGFR inhibitor, JAK inhibitor | EGFR, JAK2, JAK3 | preclinical |
Andrographolide | tumor necrosis factor production inhibitor | IL1B, IL6, NFKB1, NFKB2, TNF | 2 |
Apratastat | matrix metalloprotease inhibitor, tumor necrosis factor production inhibitor | ADAM17, MMP1, MMP13, MMP9 | 2 |
Atractylenolide-I | JAK inhibitor | JAK1, JAK2, JAK3 | preclinical |
AZD1480 | JAK inhibitor | JAK1, JAK2, JAK3 | 1 |
Balsalazide | cyclooxygenase inhibitor | ALOX5, PPARG, PTGS1, PTGS2 | launched |
BMS-911543 | JAK inhibitor | JAK1, JAK2, JAK3 | 1/2 |
Ciglitazone | PPARγ agonist | GPD1, PPARG, TBXA2R | 2 |
Curcumol | JAK inhibitor | JAK1, JAK2, JAK3 | 1 |
Cyt387 | JAK inhibitor | JAK1, JAK2, JAK3 | 3 |
Delgocitinib | JAK inhibitor | JAK1, JAK2, JAK3 | 2 |
Fedratinib | FLT3 inhibitor, JAK inhibitor | BRD4, JAK1, JAK2, JAK3, TYK2 | launched |
Filgotinib | JAK inhibitor | JAK1, JAK2, JAK3, TYK2 | 3 |
Ganoderic-acid-a | JAK inhibitor | JAK1, JAK2, JAK3 | preclinical |
JTE-607 | cytokine production inhibitor | IL10, IL1B, IL6, TNF | 2 |
Latamoxef | Cephalosporine | DACB, MRCA, MRCB, PBPC | launched |
LXR-623 | Liver X receptor agonist | AR, NR1H2, NR1H3, NR1I2, NR3C1 | 1 |
NS-018 | JAK inhibitor | JAK1, JAK2, JAK3, TYK2 | 1/2 |
Pacritinib | FLT3 inhibitor, JAK inhibitor | FLT3, JAK1, JAK2, JAK3 | 3 |
Paracetamol | cyclooxygenase inhibitor | FAAH, PTGS1, PTGS2, TRPV1 | launched |
Peficitinib | JAK inhibitor | JAK1, JAK2, JAK3 | launched |
PF-06651600 | JAK inhibitor | JAK1, JAK2, JAK3 | 2/3 |
Plerixafor | CC chemokine receptor antagonist | ACKR3, CCR4, CXCR4, MMP1, PI3 | launched |
Ruxolitinib | JAK inhibitor | JAK1, JAK2, JAK3, TYK2 | launched |
Sirolimus | mTOR inhibitor | CFD1, FKBP1A, GPD1, MMP1, MTOR, PI3, RPL38 | launched |
Tofacitinib | JAK inhibitor | JAK1, JAK2, JAK3 | launched |
Trofinetide | cytokine production inhibitor | IFNG, IL6, TNFA | 2 |
Upadacitinib | JAK inhibitor | JAK1, JAK2, JAK3 | launched |
WHI-P154 | JAK inhibitor | EGFR, JAK1, JAK2, JAK3 | preclinical |
XL019 | JAK inhibitor | JAK1, JAK2, JAK3 | 1 |
Drugs with known molecular profile registered ** or off-label administered in HS | |||
Acitretin | retinoid receptor agonist | KRT16, PI3, RARA, RARB, RARG, RBP1, RXRA, RXRB, RXRG, STAT3 | launched |
Adalimumab ** | TNF-α inhibitor | TNF | launched |
Anakinra | IL-1 receptor antagonist | IL1R1 | launched |
Avacopan | C5α receptor antagonist | C5AR1 | 2 |
Bimekizumab | IL-17A/F inhibitor | IL17A, IL17F | 3 |
Brodalumab | IL-17 receptor inhibitor | IL17R, KRT6A, S100A7A, S100A8, S100A9 | launched |
Clindamycin | Protein synthesis inhibitor | launched | |
Cyproterone acetate | AR antagonist | ADORA1, AR | launched |
Doxycycline | bacterial 30S ribosomal subunit inhibitor, metalloproteinase inhibitor | MMP1, MMP8, PI3 | launched |
Etanercept | TNF-α receptor antagonist | TNFRSF1A | launched |
Golimumab | TNF inhibitor | TNF | launched |
INCB 54707 | JAK1 inhibitor | JAK1 | 2 |
Infliximab | TNF inhibitor | IL6, TNF | launched |
Metformin | insulin sensitizer | ACACB, PRKAB1 | launched |
Rifampicin | RNA polymerase inhibitor | NR1I2, SLCO1A2, SLCO1B1, SLCO1B3 | launched |
Secukinumab | IL-17A inhibitor | IL17A | 3 |
Spesolimab | IL-36R antagonist | IL36RN | 2 |
Ustekinumab | IL12/IL23 inhibitor | FSH, HCG, LH, LTA4H | Launched |
Vilobelimab | C5α inhibitor | C5 | 2 |
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Zouboulis, V.A.; Zouboulis, K.C.; Zouboulis, C.C. Hidradenitis Suppurativa and Comorbid Disorder Biomarkers, Druggable Genes, New Drugs and Drug Repurposing—A Molecular Meta-Analysis. Pharmaceutics 2022, 14, 44. https://doi.org/10.3390/pharmaceutics14010044
Zouboulis VA, Zouboulis KC, Zouboulis CC. Hidradenitis Suppurativa and Comorbid Disorder Biomarkers, Druggable Genes, New Drugs and Drug Repurposing—A Molecular Meta-Analysis. Pharmaceutics. 2022; 14(1):44. https://doi.org/10.3390/pharmaceutics14010044
Chicago/Turabian StyleZouboulis, Viktor A., Konstantin C. Zouboulis, and Christos C. Zouboulis. 2022. "Hidradenitis Suppurativa and Comorbid Disorder Biomarkers, Druggable Genes, New Drugs and Drug Repurposing—A Molecular Meta-Analysis" Pharmaceutics 14, no. 1: 44. https://doi.org/10.3390/pharmaceutics14010044