Machine Learning Discoveries of Interleukin-X Synergy in ETC-1922159 Treated Colorectal Cancer Cells

Machine learning discoveries of Interleukin-X synergy in ETC-1922159 treated colorectal cancer cells shriprakash sinha Independent Researcher; Orcid ID : orcid.org/0000-0001-7027-5788 104-Madhurisha Heights Phase 1, Risali, Bhilai-490006, India Abstract Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combinations of factors/genes/proteins that might be affecting the pathway under certain conditions. In colorectal cancer (CRC) cells treated with ETC-1922159, many genes were found up and down regulated, individually. A recently developed search engine ranked combinations of Interleukin (IL)-X (X, a particular gene/protein) at 2nd order level after drug administration. These rankings reveal which IL-X combinations might be working synergistically in CRC. If found true, oncologists can further test the combination of interest in wet lab and determine the mechanism of functioning between the IL and X. In this research work, we cover combinations of IL with nuclear factor κB (NFκB), Potassium ion channel subfamily members (KCN), mucin (MUC), TP53, STAT, TNF receptor associated factor (TRAF), STEAP4 metalloreductase, STEAP3 metalloreductase, ATPbinding cassette (ABC) transporters and tumor necrosis factor (TNF). Keywords: Interleukin (IL), Porcupine inhibitor ETC-1922159, Sensitivity analysis, Colorectal cancer. 1. Introduction In the unpublished preprint Sinha [1], a frame work of a search engine was developed which can rank combinations of factors (genes/proteins) in a signaling pathway. Such combinations are of import due to the vast search space in which they exist and the difficulty to find them. The search engine facilitates in prioritizing the combinations5 as ranked biological hypotheses which the biologists might want to test in wet lab, to know if a synergistic combination is prevalent in a signaling pathway, in a direct or indirect manner. Interested readers are advised to go through unpublished preprints IML dicoveries of Interleukin-X synergy in ETC-1922159 treated CRC cells Email address: [email protected] (shriprakash sinha) 1Aspects of unpublished work were presented in a poster session at (1) the recently concluded first ever Wnt Gordon Conference, from 6-11 August 2017, held in Stowe, VT 05672, USA. Preprint submitted to Preprint September 2, 2024 Sinha [1] and Sinha [2] for details regarding the search engine and the discoveries mentioned in there.10 2. Materials and Methods 2.1. Combinatorial search problem and a possible solution The issue of combinatorial search problem and a possible solution has been addressed in Sinha [3] and Sinha [2]. The details of the methodology of this manuscript have been explained in great detail in Sinha [3] & its application in Sinha [2]. Readers15 are requested to go through the same for gaining deeper insight into the working of the pipeline and its use of published data set generated after administration of ETC1922159. In order to understand the significance of the solution proposed to the problem of combinatorial search that the biologists face in revealing unknown biological search problem, these works are of importance.20 Briefly, from Sinha [2], the pipleline works by computing sensitivity indicies for each of these unique combinations and then vectorising these indices to connote and form discriminative feature vector for each combination. Since each combination is unique, the training and the test data are same. In the training data, the combinations are arranged and ranks from 1 to n are assigned. The ranking algorithm then learns25 the patterns from these combinations/sensitivity index vectors. Next the learned model is used to rank the test data by generating the ranking score for each of the unique combination. Sorting these shuffled scores of test data leads to prioritization of the combinations. Joachims [4] show an example of applying learned model to training data (same as the test data) in https://www.cs.cornell.edu/people/tj/svm_30 light/svm_rank.html. Note that these combinations are now ranked and give the biologists a chance to narrow down their focus on crucial biological hypotheses in the form of combinations which the biologists might want to test. Analogous to the webpage search engine, where the click of a button for a few key-words leads to a ranked list of web links, the pipeline uses sensitivity indices as an indicator of the strength of35 the influence of factors or their combinations, as a criteria to rank the combinations. 3. Results & Discussion 3.1. Interleukin related synergies 3.1.1. NFκB-2/I - Interleukin cross family analysis H¨ orber et al. [5] show that the atypical inhibitor of NF-κB, IκBζ, controls macrophage40 interleukin-10 expression. Yamazaki et al. [6] observe that stimulus-specific induction of a novel nuclear factor-κB regulator, IκB-ζ, via Toll/Interleukin-1 receptor is mediated by mRNA stabilization. Kurzrock et al. [7] show that Interleukin-1 increases expression of the LYT-10 (NFκB2) proto-oncogene/transcription factor in renal cell carcinoma lines. These studies and many others not indicated here, show the connec-45 tion between Interleukin and NFkB-2 and NFkBI family. In CRC cells treated with 2 ETC-1922159, members of these families were UP regulated. Table 1 shows the rankings of each family with the other. On the left side, rankings of IL w.r.t NFkB-2/I has been indicated. We found IL15RA/17C to be up regulated w.r.t NFkB2. These are reflected in rankings of 1787 (rbf)50 and 1957 (rbf) IL15RA - NFkB2 and 2288 (linear) and 2018 (rbf) IL17C - NFkB2. IL1RN/6ST/15RA to be up regulated w.r.t NFkB2. These are reflected in rankings of 1753 (laplace) and 1906 (linear) for IL1RN - NFkBIA; 2400 (linear) and 2094 (rbf) for IL6ST - NFkBIA and 2251 (laplace) and 2390 (linear) for IL15RA - NFkBIA. IL1RAP/6ST/8/17REL to be up regulated w.r.t NFkB2. These are reflected in rankings55 of 2221 (linear) and 1807 (rbf) IL1RAP - NFkBIE; 2381 (linear) and 2277 (rbf) for IL6ST - NFkBIE; 2198 (linear) and 2133 (rbf) for IL8 - NFkBIE and 2216 (linear) and 2168 (rbf) for IL17REL - NFkBIE. IL-1A/6ST/15 to be up regulated w.r.t NFkB2. These are reflected in rankings of 2381 (laplace) and 2049 (linear) for IL1A - NFkBIZ; 2279 (laplace) and 2431 (linear) for IL6ST - NFkBIZ and 1780 (laplace) and 209860 (linear) for IL15 - NFkBIZ; On the right side, rankings of NFkB-2/I w.r.t IL has been indicated. We found NFkB-2 to be up regulated w.r.t IL10RB. This is reflected in rankings of 2282 (laplace), 2381 (linear) and 1897 (rbf) for NFkB2 - IL10RB. NFkBIZ to be up regulated w.r.t IL-10RB/17REL. These were reflected in rankings of 2271 (laplace) and 2082 (rbf) for65 IL10RB - NFkBIZ and 1883 (linear) and 1830 (rbf) for IL17REL - NFkBIZ. Table 2 shows the derived influences which can be represented graphically, with the following influences - •IL w.r.t NFkB with IL w.r.t NFkB-2/I with IL15RA <− NFkB2; IL17C <−NFkB2; IL1RN <−NFkBIA; IL6ST <−NFkBIA; IL15RA <− NFkBIA; IL1RAP <−NFkBIE; IL6ST <−NFkBIE; IL8 <−NFkBIE; IL17REL70 <−NFkBIE; IL1A <−NFkBIZ; IL6ST <−NFkBIZ; IL15 <−NFkBIZ; and • NFkB-2/I w.r.t IL with IL10RB −>NFkB2; IL10RB −>NFKBIZ; IL17REL −> NFkBIZ; 3 RANKING INTERLEUKIN FAMILY VS NFKB-2 FAMILY RANKING OF IL FAMILY W.R.TNFKB-2 RANKING OF NFKB-2/I W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - NFkB2 1485 6 2494 IL1A - NFkB2 616 276 1358 IL1B - NFkB2 1852 638 1587 IL1B - NFkB2 283 284 1088 IL1RAP - NFkB2 1369 1849 1463 IL1RAP - NFkB2 967 377 161 IL1RN - NFkB2 1285 1963 1604 IL1RN - NFkB2 1386 2086 52 IL2RG - NFkB2 486 1077 1300 IL2RG - NFkB2 1436 1123 2163 IL6ST - NFkB2 493 814 283 IL6ST - NFkB2 2177 343 2255 IL8 - NFkB2 1907 865 335 IL8 - NFkB2 303 2355 1152 IL10RB - NFkB2 707 1607 595 IL10RB - NFkB2 2282 2381 1897 IL15 - NFkB2 792 1113 1434 IL15 - NFkB2 2112 1214 1217 IL15RA - NFkB2 1787 233 1957 IL15RA - NFkB2 1289 1235 1913 IL17C - NFkB2 2288 305 2018 IL17C - NFkB2 380 529 1492 IL17REL - NFkB2 9 2464 167 IL17REL - NFkB2 115 1540 308 RANKING OF IL FAMILY W.R.TNFKBI-A RANKING OF NFKB-2/I W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - NFkBIA 116 46 1885 IL1A - NFkBIA 989 1179 705 IL1B - NFkBIA 328 56 1228 IL1B - NFkBIA 611 397 1378 IL1RAP - NFkBIA 1376 778 359 IL1RAP - NFkBIA 1131 515 1887 IL1RN - NFkBIA 1753 1906 267 IL1RN - NFkBIA 2357 578 382 IL2RG - NFkBIA 32 6 898 IL2RG - NFkBIA 132 684 784 IL6ST - NFkBIA 1011 2400 2094 IL6ST - NFkBIA 2008 533 90 IL8 - NFkBIA 1988 1234 1232 IL8 - NFkBIA 183 993 1109 IL10RB - NFkBIA 864 2239 8 IL10RB - NFkBIA 616 1251 107 IL15 - NFkBIA 1181 453 462 IL15 - NFkBIA 2227 958 165 IL15RA - NFkBIA 2251 2390 1652 IL15RA - NFkBIA 765 291 2301 IL17C - NFkBIA 538 229 330 IL17C - NFkBIA 450 178 19 IL17REL - NFkBIA 643 16 4 IL17REL - NFkBIA 1275 403 2190 RANKING OF IL FAMILY W.R.TNFKBI-E RANKING OF NFKBI-E W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - NFkBIE 2486 27 76 IL1A - NFkBIE 433 1574 953 IL1B - NFkBIE 2089 39 311 IL1B - NFkBIE 1103 507 1931 IL1RAP - NFkBIE 201 2221 1807 IL1RAP - NFkBIE 474 1404 875 IL1RN - NFkBIE 2025 610 1153 IL1RN - NFkBIE 2051 381 468 IL2RG - NFkBIE 1141 986 654 IL2RG - NFkBIE 1327 1464 983 IL6ST - NFkBIE 1155 2381 2277 IL6ST - NFkBIE 309 143 939 IL8 - NFkBIE 259 2198 2133 IL8 - NFkBIE 1507 911 67 IL10RB - NFkBIE 1730 191 310 IL10RB - NFkBIE 305 478 1960 IL15 - NFkBIE 1922 365 117 IL15 - NFkBIE 2476 783 1302 IL15RA - NFkBIE 1912 839 1385 IL15RA - NFkBIE 424 526 1423 IL17C - NFkBIE 2179 105 404 IL17C - NFkBIE 2231 1205 321 IL17REL - NFkBIE 13 2216 2168 IL17REL - NFkBIE 333 831 949 RANKING OF IL FAMILY W.R.TNFKBI-Z RANKING OF NFKBI-Z W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - NFkBIZ 2381 2049 1578 IL1A - NFkBIZ 157 792 1460 IL1B - NFkBIZ 1241 2210 463 IL1B - NFkBIZ 586 217 1617 IL1RAP - NFkBIZ 694 1077 936 IL1RAP - NFkBIZ 1326 240 1080 IL1RN - NFkBIZ 860 2151 231 IL1RN - NFkBIZ 2463 739 579 IL2RG - NFkBIZ 1362 2054 68 IL2RG - NFkBIZ 68 829 1212 IL6ST - NFkBIZ 2279 980 2431 IL6ST - NFkBIZ 996 1223 140 IL8 - NFkBIZ 992 1732 966 IL8 - NFkBIZ 816 1510 119 IL10RB - NFkBIZ 717 2275 571 IL10RB - NFkBIZ 2271 42 2082 IL15 - NFkBIZ 1780 2098 626 IL15 - NFkBIZ 2155 200 245 IL15RA - NFkBIZ 633 1726 2422 IL15RA - NFkBIZ 834 1284 1785 IL17C - NFkBIZ 1716 2430 1098 IL17C - NFkBIZ 848 1282 1391 IL17REL - NFkBIZ 14 75 314 IL17REL - NFkBIZ 289 1883 1830 Table 1: 2nd order combinatorial hypotheses between NFkB-2/I and IL 4 UNEXPLORED COMBINATORIAL HYPOTHESES IL w.r.t NFkB-2/I IL15RA NFkB2 IL17C NFkB2 IL1RN NFkBIA IL6ST NFkBIA IL15RA NFkBIA IL1RAP NFkBIE IL6ST NFkBIE IL8 NFkBIE IL17REL NFkBIE IL1A NFkBIZ IL6ST NFkBIZ IL15 NFkBIZ NFkB-2/I w.r.t IL IL10RB NFkB2 IL10RB NFKBIZ IL17REL NFkBIZ Table 2: 2nd order combinatorial hypotheses between IL and NFkB-2/I family. 5 3.1.2. Potassium channel - Interleukin cross family analysis In 1986, Lee et al. [8] showed that increased voltage-gated potassium conductance75 during interleukin 2-stimulated proliferation of a mouse helper T lymphocyte clone. Martin et al. [9] show that interleukin-4 activates large-conductance, calcium-activated potassium (BKCa) channels in human airway smooth muscle cells. However, the author is not aware of deep studies between the Potassium ion channel subfamily members (KCN) and interleukin. In CRC cells treated with ETC-1922159, these were found80 to be UP regulated. The search engine found alotted multiple combinations between the members of these two families. These were reflected in ranking of the each with the other in the following table 3 and 4. On the left is rankings of IL family with respect to the KCN family member and on the right, vice versa. Beginning on the left side we found IL-1A/1B/15RA/17C to be up regulated w.r.t85 KCND3. These are reflected in rankings of 1995 (laplace) and 2255 (linear) for IL1A - KCND3; 2083 (laplace) and 1897 (linear) for IL1B - KCND3; 2074 (laplace) and 2495 (rbf) for IL15RA - KCND3; and 1881 (laplace) and 2139 (linear) for IL17C - KCND3. IL-1A/1B to be up regulated w.r.t KCNH2. These are reflected in rankings of 2103 (laplace) and 1832 (linear) for IL1A - KCNH2 and 2447 (laplace) and 206890 (linear) for IL1B - KCNH2; IL-1A/1B/17C to be up regulated w.r.t KCNH8. These are reflected in rankings of 2268 (laplace), 2507 (linear) and 1877 (rbf) for IL1A - KCNH8; 2223 (laplace), 2013 (linear) and 2204 (rbf) for IL1B - KCNH8; and 1847 (laplace), and 2354 (rbf) for IL17C - KCNH8. IL-1A/1B/1RN/15 to be up regulated w.r.t KCNK1. These are reflected in rankings of 2290 (laplace) and 2066 (linear) for95 IL1A - KCNK1; 1941 (laplace) and 2452 (linear) and 1905 (rbf) for IL1B - KCNK1; 2468 (laplace) and 1897 (linear) for IL1RN - KCNK1; 2280 (laplace) and 2009 (rbf) for IL15 - KCNK1. IL-1RN/10RB/17REL to be up regulated w.r.t KCNK5. These are reflected in rankings of 1930 (linear) and 2136 (rbf) for IL1RN-KCNK5; 1879 (laplace), 2298 (linear) and 1903 (rbf) for IL10RB-KCKK5; and 2118 (laplace) and100 1873 (rbf) for IL17REL - KCNK5; IL-8/17REL to be up regulated w.r.t KCNK5. These are reflected in rankings of 2168 (laplace) and 2442 (linear) for IL8 - KCNK6; and 2066 (laplace) and 2159 (linear) for IL17REL - KCNK6. Beginning on the right side we found KCND3 to be up regulated w.r.t IL-1A/1B/15RA/17C. These are reflected in rankings of 2495 (laplace), 2390 (linear) for IL1RAP - KCND3;105 2048 (laplace), 2306 (linear) and 2197 (rbf) for IL10RB - KCND3 and 2511 (laplace) and 2517 (linear) for IL15RA - KCND3; KCNH2 to be up regulated w.r.t IL-1A/1RAP. These are reflected in rankings of 1897 (laplace), 2152 (linear) and 2179 (rbf) for IL1A - KCNH2; and 2451 (laplace), 1805 (linear) and 2002 (rbf) for IL1RAP - KCNH2; KCNH8 to be up regulated w.r.t IL-1B/10RB. These are reflected in rankings of 2060110 (laplace) and 2177 (rbf) for IL1B - KCNH8; and 2381 (laplace) and 2008 (linear) for IL10RB - KCNH8; KCNK1 to be up regulated w.r.t IL-1A/6ST/8. These are reflected in rankings of 1818 (linear) and 2362 (rbf) for IL1A - KCNK1; 2226 (laplace) and 2283 (rbf) for IL6ST - KCNK1; and 1872 (laplace) and 1978 (linear) for IL8 - KCNK1; KCNK5 to be up regulated w.r.t IL-10RB. This is reflected in rankings of115 1769 (linear) and 2206 (rbf) for IL10RB - KCNK5; KCNK6 to be up regulated w.r.t IL-1RAP/10RB/15. These are reflected in rankings of 2386 (laplace) and 2053 (rbf) for IL1RAP - KCNK6; 1903 (linear) and 2156 (rbf) for IL10RB - KCNK6; and 1944 6 RANKING INTERLEUKIN FAMILY VS KCN FAMILY RANKING OF IL FAMILY W.R.TKCND3 RANKING OF KCND3 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - KCND3 1995 2255 718 IL1A - KCND3 707 118 11 IL1B - KCND3 2083 1897 691 IL1B - KCND3 1064 411 133 IL1RAP - KCND3 212 1086 1690 IL1RAP - KCND3 2495 2390 114 IL1RN - KCND3 1091 1875 1551 IL1RN - KCND3 459 743 300 IL2RG - KCND3 2027 1557 403 IL2RG - KCND3 588 248 58 IL6ST - KCND3 28 24 2501 IL6ST - KCND3 1 1127 2482 IL8 - KCND3 46 1098 1426 IL8 - KCND3 1134 1639 890 IL10RB - KCND3 1573 2172 1302 IL10RB - KCND3 2048 2306 2197 IL15 - KCND3 1905 1606 716 IL15 - KCND3 296 68 240 IL15RA - KCND3 2074 483 2495 IL15RA - KCND3 2511 2517 1606 IL17C - KCND3 1881 2139 368 IL17C - KCND3 588 1383 277 IL17REL - KCND3 1715 2242 359 IL17REL - KCND3 1361 748 1905 RANKING OF IL FAMILY W.R.TKCNH2 RANKING OF KCNH2 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - KCNH2 2103 1832 356 IL1A - KCNH2 1897 2152 2179 IL1B - KCNH2 2447 2068 930 IL1B - KCNH2 1599 2025 653 IL1RAP - KCNH2 423 1275 2487 IL1RAP - KCNH2 2451 1805 2002 IL1RN - KCNH2 1600 828 779 IL1RN - KCNH2 233 2304 305 IL2RG - KCNH2 1501 903 929 IL2RG - KCNH2 823 701 1820 IL6ST - KCNH2 1016 1565 1929 IL6ST - KCNH2 435 1665 2142 IL8 - KCNH2 863 258 1395 IL8 - KCNH2 1103 1062 2255 IL10RB - KCNH2 1238 1335 1441 IL10RB - KCNH2 648 1445 1684 IL15 - KCNH2 2295 1419 1038 IL15 - KCNH2 389 1247 1033 IL15RA - KCNH2 1738 2263 296 IL15RA - KCNH2 515 1572 2265 IL17C - KCNH2 2084 1399 49 IL17C - KCNH2 1388 1021 1079 IL17REL - KCNH2 90 1956 1491 IL17REL - KCNH2 727 2338 524 RANKING OF IL FAMILY W.R.TKCNH8 RANKING OF KCNH8 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - KCNH8 2268 2507 1877 IL1A - KCNH8 29 1939 1438 IL1B - KCNH8 2223 2013 2204 IL1B - KCNH8 2060 472 2177 IL1RAP - KCNH8 1238 479 1717 IL1RAP - KCNH8 1950 651 150 IL1RN - KCNH8 1653 819 2040 IL1RN - KCNH8 1094 329 988 IL2RG - KCNH8 57 1530 651 IL2RG - KCNH8 1853 1224 390 IL6ST - KCNH8 2067 979 1640 IL6ST - KCNH8 607 368 800 IL8 - KCNH8 1558 439 1250 IL8 - KCNH8 2484 269 1048 IL10RB - KCNH8 937 448 416 IL10RB - KCNH8 2381 2008 726 IL15 - KCNH8 1575 1789 580 IL15 - KCNH8 1365 1649 2187 IL15RA - KCNH8 2082 1524 1550 IL15RA - KCNH8 1667 638 1648 IL17C - KCNH8 1847 1700 2354 IL17C - KCNH8 1232 1825 1519 IL17REL - KCNH8 1542 2 1803 IL17REL - KCNH8 1120 681 2060 Table 3: 2nd order combinatorial hypotheses between KCN and IL (laplace) and 2047 (rbf) for IL15 - KCNK6; Finally, table 5shows the derived influences which can be represented graphically,120 with the following influences - •IL w.r.t KCN with IL-1A/1B/15RA/17C <−KCND3; 7 RANKING INTERLEUKIN FAMILY VS KCN FAMILY RANKING OF IL FAMILY W.R.TKCNK1 RANKING OF KCNK1 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - KCNK1 2290 2066 1071 IL1A - KCNK1 1644 1818 2362 IL1B - KCNK1 1941 2452 1905 IL1B - KCNK1 813 966 1554 IL1RAP - KCNK1 171 595 2490 IL1RAP - KCNK1 1103 1318 1803 IL1RN - KCNK1 2468 1897 391 IL1RN - KCNK1 2130 73 1326 IL2RG - KCNK1 2384 1028 755 IL2RG - KCNK1 650 2324 1413 IL6ST - KCNK1 862 131 807 IL6ST - KCNK1 2226 688 2283 IL8 - KCNK1 722 22 2147 IL8 - KCNK1 1872 1978 1201 IL10RB - KCNK1 1965 125 1204 IL10RB - KCNK1 1087 1633 1021 IL15 - KCNK1 2280 2009 502 IL15 - KCNK1 1639 506 2369 IL15RA - KCNK1 1567 1546 895 IL15RA - KCNK1 1126 1499 784 IL17C - KCNK1 2451 122 931 IL17C - KCNK1 1331 2472 611 IL17REL - KCNK1 1515 659 2391 IL17REL - KCNK1 979 2329 329 RANKING OF IL FAMILY W.R.TKCNK5 RANKING OF KCNK5 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - KCNK5 609 608 796 IL1A - KCNK5 1840 1512 576 IL1B - KCNK5 1297 110 543 IL1B - KCNK5 510 1379 347 IL1RAP - KCNK5 1137 2237 1314 IL1RAP - KCNK5 730 911 1003 IL1RN - KCNK5 1583 1930 2136 IL1RN - KCNK5 815 405 1431 IL2RG - KCNK5 223 601 14 IL2RG - KCNK5 1841 782 806 IL6ST - KCNK5 1038 867 295 IL6ST - KCNK5 455 848 1275 IL8 - KCNK5 819 1737 105 IL8 - KCNK5 272 479 1215 IL10RB - KCNK5 1879 2298 1903 IL10RB - KCNK5 457 1769 2206 IL15 - KCNK5 981 1630 1669 IL15 - KCNK5 1060 244 580 IL15RA - KCNK5 791 124 555 IL15RA - KCNK5 361 332 1662 IL17C - KCNK5 2345 449 919 IL17C - KCNK5 388 713 509 IL17REL - KCNK5 18 2118 1873 IL17REL - KCNK5 1377 2108 1634 RANKING OF IL FAMILY W.R.TKCNK6 RANKING OF KCNK6 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - KCNK6 140 180 615 IL1A - KCNK6 1683 944 860 IL1B - KCNK6 525 57 369 IL1B - KCNK6 620 1047 903 IL1RAP - KCNK6 1878 830 902 IL1RAP - KCNK6 2386 1248 2053 IL1RN - KCNK6 1834 1564 90 IL1RN - KCNK6 2047 970 1311 IL2RG - KCNK6 2181 974 7 IL2RG - KCNK6 691 2454 1443 IL6ST - KCNK6 728 1895 1270 IL6ST - KCNK6 440 125 1682 IL8 - KCNK6 2168 2442 869 IL8 - KCNK6 774 98 654 IL10RB - KCNK6 1821 560 85 IL10RB - KCNK6 802 1903 2156 IL15 - KCNK6 1589 304 2447 IL15 - KCNK6 1944 130 2047 IL15RA - KCNK6 87 436 2447 IL15RA - KCNK6 1835 1531 1529 IL17C - KCNK6 103 200 538 IL17C - KCNK6 1056 1350 1408 IL17REL - KCNK6 2066 2159 1735 IL17REL - KCNK6 1044 1263 947 Table 4: 2nd order combinatorial hypotheses between KCN and IL IL-1A/1B <−KCNH2; IL-1A/1B/17C <−KCNH8; IL-1A/1B/1RN/15 <−KCNK1; IL-1RN/10RB/17REL <−KCNK5; IL-8/17REL <−KCNK6; and •KCN w.r.t IL family with IL-1A/1B/15RA/17C −>KCND3; IL-1A/1RAP −>KCNH2; IL8 UNEXPLORED COMBINATORIAL HYPOTHESES IL w.r.t KCN IL-1A/1B/15RA/17C KCND3 IL-1A/1B KCNH2 IL-1A/1B/17C KCNH8 IL-1A/1B/1RN/15 KCNK1 IL-1RN/10RB/17REL KCNK5 IL-8/17REL KCNK6 KCN w.r.t IL family IL-1A/1B/15RA/17C KCND3 IL-1A/1RAP KCNH2 IL-1B/10RB KCNH8 IL-1A/6ST/8 KCNK1 IL-10RB KCNK5 IL-1RAP/10RB/15 KCNK6 Table 5: 2nd order combinatorial hypotheses between IL family w.r.t KCN family. 1B/10RB −>KCNH8; IL-1A/6ST/8 −>KCNK1; IL-10RB −>KCNK5; and IL-125 1RAP/10RB/15 −>KCNK6; 9 RANKING INTERLEUKIN FAMILY VS TP53 FAMILY RANKING OF IL FAMILY W.R.TTP53BP2 RANKING OF TP53BP2 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TP53BP2 2396 1377 302 IL1A - TP53BP2 390 2306 2483 IL1B - TP53BP2 1868 1606 16 IL1B - TP53BP2 2003 1319 2317 IL1RAP - TP53BP2 154 1863 1166 IL1RAP - TP53BP2 1565 1196 133 IL1RN - TP53BP2 320 1676 1920 IL1RN - TP53BP2 1559 1149 2489 IL2RG - TP53BP2 755 377 644 IL2RG - TP53BP2 1842 1888 1791 IL6ST - TP53BP2 2237 581 1526 IL6ST - TP53BP2 1862 1530 2234 IL8 - TP53BP2 1135 1279 2250 IL8 - TP53BP2 2356 2336 325 IL10RB - TP53BP2 645 977 289 IL10RB - TP53BP2 420 705 2040 IL15 - TP53BP2 1715 281 973 IL15 - TP53BP2 879 2029 1896 IL15RA - TP53BP2 1225 727 567 IL15RA - TP53BP2 2086 2287 2198 IL17C - TP53BP2 2286 1214 617 IL17C - TP53BP2 1158 1243 2313 IL17REL - TP53BP2 76 1873 2403 IL17REL - TP53BP2 1526 1463 1600 RANKING OF IL FAMILY W.R.TTP53I3 RANKING OF TP53I3 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TP53I3 1140 1547 1558 IL1A - TP53I3 283 157 341 IL1B - TP53I3 759 333 1392 IL1B - TP53I3 156 164 463 IL1RAP - TP53I3 1521 885 1978 IL1RAP - TP53I3 432 605 818 IL1RN - TP53I3 737 340 1797 IL1RN - TP53I3 1504 1674 16 IL2RG - TP53I3 7 3 328 IL2RG - TP53I3 836 637 134 IL6ST - TP53I3 524 363 981 IL6ST - TP53I3 2157 897 778 IL8 - TP53I3 579 485 697 IL8 - TP53I3 1921 290 1265 IL10RB - TP53I3 185 137 758 IL10RB - TP53I3 345 1080 326 IL15 - TP53I3 240 244 428 IL15 - TP53I3 353 1153 456 IL15RA - TP53I3 2069 2079 2228 IL15RA - TP53I3 106 644 1794 IL17C - TP53I3 74 114 647 IL17C - TP53I3 49 75 37 IL17REL - TP53I3 597 326 1290 IL17REL - TP53I3 2268 429 2220 RANKING OF IL FAMILY W.R.TTP53INP1 RANKING OF TP53INP1 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TP53INP1 2309 746 7 IL1A - TP53INP1 1049 1135 1138 IL1B - TP53INP1 2281 21 461 IL1B - TP53INP1 1395 1370 1684 IL1RAP - TP53INP1 531 1274 2407 IL1RAP - TP53INP1 2223 1460 680 IL1RN - TP53INP1 2482 1911 891 IL1RN - TP53INP1 1473 1252 2399 IL2RG - TP53INP1 2152 1798 932 IL2RG - TP53INP1 2063 1864 1956 IL6ST - TP53INP1 591 790 1740 IL6ST - TP53INP1 537 404 2042 IL8 - TP53INP1 573 2388 2343 IL8 - TP53INP1 1671 1787 1014 IL10RB - TP53INP1 2510 2293 1664 IL10RB - TP53INP1 1000 2339 218 IL15 - TP53INP1 663 878 1116 IL15 - TP53INP1 2147 588 429 IL15RA - TP53INP1 663 149 169 IL15RA - TP53INP1 1266 2264 1636 IL17C - TP53INP1 2455 220 435 IL17C - TP53INP1 823 523 438 IL17REL - TP53INP1 83 2505 2509 IL17REL - TP53INP1 1085 1476 1393 RANKING OF IL FAMILY W.R.TTP53INP2 RANKING OF TP53INP2 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TP53INP2 1481 41 2490 IL1A - TP53INP2 952 505 487 IL1B - TP53INP2 489 310 267 IL1B - TP53INP2 200 26 146 IL1RAP - TP53INP2 1159 684 1263 IL1RAP - TP53INP2 1168 757 1827 IL1RN - TP53INP2 2374 779 110 IL1RN - TP53INP2 1735 1927 264 IL2RG - TP53INP2 2118 103 995 IL2RG - TP53INP2 1151 539 380 IL6ST - TP53INP2 261 1459 333 IL6ST - TP53INP2 2512 1952 113 IL8 - TP53INP2 82 679 779 IL8 - TP53INP2 2349 85 1561 IL10RB - TP53INP2 865 1991 67 IL10RB - TP53INP2 653 2479 236 IL15 - TP53INP2 1354 989 161 IL15 - TP53INP2 1105 449 1506 IL15RA - TP53INP2 1574 1545 2295 IL15RA - TP53INP2 345 488 825 IL17C - TP53INP2 449 56 221 IL17C - TP53INP2 1065 260 116 IL17REL - TP53INP2 1325 93 593 IL17REL - TP53INP2 1251 643 1832 Table 9: 2nd order combinatorial hypotheses between TP53 and IL 16 UNEXPLORED COMBINATORIAL HYPOTHESES IL w.r.t TP53 IL17REL TP53BP2 IL15RA TP53I3 IL-1RN/2RG/8/10RB/17REL TP53INP1 TP53 w.r.t IL IL-1A/1B/2RG/6ST/8/15/15RA TP53BP2 IL17REL TP53I3 IL2RG TP53INP1 IL6ST TP53INP2 Table 10: 2nd order combinatorial hypotheses between IL and NFkB-2/I family. 17 3.1.5. Interleukin - STAT cross family analysis220 Jones et al. [21] study the roles of interleukin-6 in activation of STAT proteins and recruitment of neutrophils during Escherichia coli pneumonia. Characterization of the interleukin-4 nuclear activated factor/STAT and its activation independent of the insulin receptor substrate proteins have been studied by Kotanides et al. [22]. Adam et al. [23] have unraveled viral interleukin-6 binding to gp130 and activation of STAT-signaling225 pathways independently of the interleukin-6 receptor. Frank et al. [24] report the involvement of interleukin 2 signaling in phosphorylation of Stat proteins. Boyd et al. [25] show that interleukin-10 receptor signaling through STAT-3 regulates the apoptosis of retinal ganglion cells in response to stress. Essential role of endocytosis for interleukin-4-receptor-mediated JAK/STAT signalling has been studied in Kurgonaite230 et al. [26]. Contribution of the interleukin-6/STAT-3 signaling pathway to chondrogenic differentiation of human mesenchymal stem cells has been studied in Kondo et al. [27]. Tanaka et al. [28] show interleukin-10 induces inhibitory C/EBPβthrough STAT-3 and represses HIV-1 transcription in macrophages. Jobst et al. [29] show that inhibition of interleukin-3-and interferon-α-induced JAK/STAT signaling by the syn-235 thetic α-X-2’, 3, 4, 4’-tetramethoxychalcones α-Br-TMC and α-CF3-TMC. These indicate significant interaction between interleukin family and the STAT family. In CRC cells, treated with ETC-1922159 both were found to be up regulated. The search engine alotted high numerical ranked values to some of the 2nd order combinations between the two. Table 11 indicates the rankings of IL family w.r.t STAT2 family on the left and240 vice versa on the right. On the left side, we found IL-1RAP/6ST/17REL to be up regulated with respect to STAT2. These are reflected in rankings of 2111 (laplace), 2258 (linear) and 2012 (rbf) for IL1RAP - STAT2; 2167 (laplace) and 2313 (linear) for IL6ST - STAT2; and 2508 (laplace), 2488 (linear) and 2172 (rbf) for IL17REL - STAT2. IL-1RAP/17REL245 were up regulated with respect to STAT3. These are reflected in rankings of 2252 (linear) and 2211 (rbf) for IL1RAP - STAT3; and 2282 (linear) and 2517 (rbf) for IL17REL - STAT3; IL-1RAP/15RA were up regulated with respect to STAT5A. These are reflected in rankings of 1768 (laplace) and 2149 (linear) for IL1RAP - STAT5A; and 2342 (laplace) and 2350 (linear) for IL15RA - STAT5A.250 On the right side, we found STAT2 to be up regulated with respect to IL-1RAP/1RN/2RG/15RA/17C/17REL. These are reflected in rankings of 1826 (laplace) and 2005 (linear) for IL1RAP - STAT2; 2050 (laplace) 2082 (linear) for IL1RN - STAT2; 1986 (laplace) 2021 (linear) and 2031 (rbf) for IL2RG - STAT2; 1988 (linear) and 1863 (rbf) for IL15RA - STAT2; 2473 (linear) and 1883 (rbf) for IL17C - STAT2; 1890 (linear) and 1885 (rbf)255 for IL17REL - STAT2. STAT3 was up regulated with respect to IL-1RN/2RG. These are reflected in rankings of 2090 (laplace) and 2312 (linear) for IL1RN - STAT3; and 2233 (laplace) and 2146 (linear) IL2RG - STAT3. STAT5A was up regulated with respect to IL-2RG/8/17C. These are reflected in rankings of 1832 (linear) and 2149 (rbf) for IL2RG - STAT5A; 2000 (laplace) and 2386 (linear) for IL8 - STAT5A; and 1760260 (laplace), 2060 (linear) and 2201 (rbf) for IL17C - STAT5A. Finally, table 12 shows the derived influences which can be represented graphically, with the following influences - •IL w.r.t STAT with IL-1RAP/6ST/17REL <− STAT2; IL-1RAP/17REL <−STAT3 and IL-1RAP/15RA <−STAT5A; and •STAT 18 RANKING INTERLEUKIN FAMILY VS STAT FAMILY RANKING OF IL FAMILY W.R.TSTAT2 RANKING OF STAT2 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - STAT2 171 207 709 IL1A - STAT2 1000 687 1941 IL1B - STAT2 347 559 188 IL1B - STAT2 1629 1019 2351 IL1RAP - STAT2 2111 2258 2012 IL1RAP - STAT2 1826 2005 70 IL1RN - STAT2 828 1942 1226 IL1RN - STAT2 2050 2082 1030 IL2RG - STAT2 939 1424 272 IL2RG - STAT2 1986 2021 2031 IL6ST - STAT2 2167 2313 1042 IL6ST - STAT2 1532 1766 696 IL8 - STAT2 806 1012 69 IL8 - STAT2 397 1015 2349 IL10RB - STAT2 1093 2401 1260 IL10RB - STAT2 1566 1241 467 IL15 - STAT2 929 197 446 IL15 - STAT2 1875 1724 940 IL15RA - STAT2 537 415 1916 IL15RA - STAT2 1406 1988 1863 IL17C - STAT2 175 78 514 IL17C - STAT2 1199 2473 1883 IL17REL - STAT2 2508 2488 2172 IL17REL - STAT2 244 1890 1885 RANKING OF IL FAMILY W.R.TSTAT3 RANKING OF STAT3 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - STAT3 2516 173 7 IL1A - STAT3 1872 1289 2350 IL1B - STAT3 1628 127 613 IL1B - STAT3 1367 2391 901 IL1RAP - STAT3 23 2252 2211 IL1RAP - STAT3 2169 1483 179 IL1RN - STAT3 2309 300 488 IL1RN - STAT3 2090 2312 1440 IL2RG - STAT3 1168 397 611 IL2RG - STAT3 2233 2146 1387 IL6ST - STAT3 1355 1217 381 IL6ST - STAT3 2400 2491 1953 IL8 - STAT3 2353 740 1176 IL8 - STAT3 1371 942 2018 IL10RB - STAT3 2494 1257 1320 IL10RB - STAT3 1118 406 1299 IL15 - STAT3 2164 903 62 IL15 - STAT3 2015 2412 1356 IL15RA - STAT3 1140 1572 1618 IL15RA - STAT3 1724 1638 1963 IL17C - STAT3 2437 30 20 IL17C - STAT3 554 1446 1428 IL17REL - STAT3 339 2282 2517 IL17REL - STAT3 573 2181 521 RANKING OF IL FAMILY W.R.TSTAT5A RANKING OF STAT5A W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - STAT5A 1631 1110 2210 IL1A - STAT5A 275 464 1645 IL1B - STAT5A 1194 1561 2223 IL1B - STAT5A 416 240 1659 IL1RAP - STAT5A 1768 1680 2149 IL1RAP - STAT5A 1852 391 432 IL1RN - STAT5A 119 285 908 IL1RN - STAT5A 86 2026 960 IL2RG - STAT5A 1136 1088 1435 IL2RG - STAT5A 1367 1832 2149 IL6ST - STAT5A 1441 2022 1697 IL6ST - STAT5A 1903 436 317 IL8 - STAT5A 1932 1543 1069 IL8 - STAT5A 2000 2386 4 IL10RB - STAT5A 897 87 2033 IL10RB - STAT5A 2103 1292 1326 IL15 - STAT5A 1116 801 1653 IL15 - STAT5A 436 2139 1041 IL15RA - STAT5A 2342 2350 788 IL15RA - STAT5A 621 1185 1537 IL17C - STAT5A 984 1386 2045 IL17C - STAT5A 1760 2060 2201 IL17REL - STAT5A 1308 755 3 IL17REL - STAT5A 477 369 992 Table 11: 2nd order combinatorial hypotheses between STAT and IL w.r.t IL with IL-1RN/2RG −>STAT2; IL-1A/1RN/2RG/6ST/15 −>STAT3 and IL-265 2RG/8/17C −>STAT5A; 19 UNEXPLORED COMBINATORIAL HYPOTHESES IL w.r.t STAT IL-1RAP/6ST/17REL STAT2 IL-1RAP/17REL STAT3 IL-1RAP/15RA STAT5A STAT w.r.t IL IL-1RN/2RG STAT2 IL-1A/1RN/2RG/6ST/15 STAT3 IL-2RG/8/17C STAT5A Table 12: 2nd order combinatorial hypotheses between IL and STAT family. 20 3.1.6. Interleukin - TRAF cross family analysis Greene and O’Neill [30] show that interleukin-1 receptor-associated kinase and TRAF6 mediate the transcriptional regulation of interleukin-2 by interleukin-1 via NFκB but unlike interleukin-1 are unable to stabilise interleukin-2 mRNA. Cao et al. [31]270 observe that TRAF6 is a signal transducer for interleukin-1. Schwandner et al. [32] show the requirement of tumor necrosis factor receptor-associated factor (TRAF) 6 in interleukin 17 signal transduction. Lomaga et al. [33] show that TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Jefferies et al. [34] observe that transactivation by the p65 subunit of NF-κB in response to275 interleukin-1 (IL-1) involves MyD88, IL-1 receptor-associated kinase 1, TRAF-6, and Rac1. Wu and Arron [35] study the role of TRAF6 as a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology and find relation with the interleukin-1 receptor family. These findings indicate the range of interaction between IL family and TRAF family. In CRC cells treated with ETC-1922159, these were found280 to be UP regulated. Table 13 show the rankings of IL family w.r.t TRAF family on the left side and vice versa on the right side. On the left we found, we found IL-1RAP/15RA/17REL to be up regulated with respect to TRAF3IP2. These are reflected in rankings of 2482 (linear) and 2385 (rbf) for IL1RAP - TRAF3IP2; 2024 (laplace), 2162 (linear) and 1800 (rbf) for IL15RA -285 TRAF3IP2; and 2515 (linear) and 2057 (rbf) for IL17REL - TRAF3IP2. IL-6ST/17REL were up regulated with respect to TRAF4. These are reflected in rankings of 2333 (laplace) and 1914 (rbf) for IL6ST - TRAF4; and (laplace) and 2487 (rbf) for IL17REL - TRAF4 2422; IL-8/17REL were up regulated with respect to TRAF6. These are reflected in rankings of 2088 (laplace), 1883 (linear) and 2089 (rbf) for IL8 - TRAF6;290 and 2454 (laplace) and 2517 (linear) for IL17REL - TRAF6; IL-6ST were up regulated with respect to TRAFD1. These are reflected in rankings of 1835 (laplace) and 1824 (linear) for IL6ST - TRAFD1. On the right we found, we found TRAF3IP2 was up regulated with respect to IL-1B/2RG/6ST/8/17REL. These are reflected in rankings of 1953 (laplace) and 2359295 (rbf) for IL1B - TRAF3IP2; 1767 (laplace), 2385 (linear) and 2059 (rbf) for IL2RG - TRAF3IP2; 1991 (linear) and 1871 (rbf) for IL6ST - TRAF3IP2; 2192 (linear) and 2289 (rbf) for IL8 - TRAF3IP2; and 1836 (laplace) and 2042 (linear) for IL17REL - TRAF3IP2. TRAF4 was up regulated with respect to IL-10RB/15/15RA. These are reflected in rankings of 2407 (laplace) and 1781 (linear) for IL10RB - TRAF4; 2408300 (linear) and 1759 (rbf) for IL15 - TRAF4; and 2408 (linear) and 1759 (rbf) for IL15RA - TRAF4; TRAF6 was up regulated with respect to IL-1RAP/8/15/17C. These are reflected in rankings of 2219 (laplace), 1984 (linear) and 1766 (rbf) for IL1RAP - TRAF6; 2457 (laplace) and 2139 (linear) for IL8 - TRAF6; 2071 (lapalce) and 2475 (linear) for IL15 - TRAF6; and 2469 (laplace) and 2309 (linear) for IL17C - TRAF6;305 Finally, table 14 shows the derived influences which can be represented graphically, with the following influences - •IL w.r.t TRAF with IL-1RAP/15RA/17REL <− TRAF3IP2; IL-6ST/17REL <−TRAF4; IL-8/17REL <−TRAF6; and IL-6ST <− TRAFD1; and •TRAF w.r.t IL with IL-1B/2RG/6ST/8/17REL −>TRAF3IP2; IL10RB/15/15RA −>TRAF4 and IL-1RAP/8/15/17C −>TRAF6.310 21 RANKING INTERLEUKIN FAMILY VS TRAF FAMILY RANKING OF IL FAMILY W.R.TTRAF3IP2 RANKING OF TRAF3IP2 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TRAF3IP2 2142 100 666 IL1A - TRAF3IP2 1518 2265 1107 IL1B - TRAF3IP2 1155 110 1193 IL1B - TRAF3IP2 1953 1294 2359 IL1RAP - TRAF3IP2 704 2482 2385 IL1RAP - TRAF3IP2 913 2034 38 IL1RN - TRAF3IP2 272 497 133 IL1RN - TRAF3IP2 1044 538 1173 IL2RG - TRAF3IP2 1948 1043 942 IL2RG - TRAF3IP2 1767 2385 2059 IL6ST - TRAF3IP2 49 1244 1098 IL6ST - TRAF3IP2 257 1991 1871 IL8 - TRAF3IP2 1165 598 344 IL8 - TRAF3IP2 796 2192 2289 IL10RB - TRAF3IP2 1252 1426 552 IL10RB - TRAF3IP2 840 237 2096 IL15 - TRAF3IP2 1550 433 163 IL15 - TRAF3IP2 1428 1183 2219 IL15RA - TRAF3IP2 2024 2162 1800 IL15RA - TRAF3IP2 906 1995 1717 IL17C - TRAF3IP2 2253 61 98 IL17C - TRAF3IP2 1290 1587 1839 IL17REL - TRAF3IP2 18 2515 2057 IL17REL - TRAF3IP2 1836 2042 1568 RANKING OF IL FAMILY W.R.TTRAF4 RANKING OF TRAF4 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TRAF4 26 2316 707 IL1A - TRAF4 1806 439 1465 IL1B - TRAF4 582 2136 175 IL1B - TRAF4 1026 746 378 IL1RAP - TRAF4 1180 1714 961 IL1RAP - TRAF4 909 2225 1546 IL1RN - TRAF4 494 2347 590 IL1RN - TRAF4 625 1031 1939 IL2RG - TRAF4 1092 1860 275 IL2RG - TRAF4 1130 339 826 IL6ST - TRAF4 2333 344 1914 IL6ST - TRAF4 676 1966 1556 IL8 - TRAF4 749 604 950 IL8 - TRAF4 406 450 1531 IL10RB - TRAF4 580 2512 424 IL10RB - TRAF4 2407 1781 1136 IL15 - TRAF4 1131 2078 227 IL15 - TRAF4 905 2408 1759 IL15RA - TRAF4 551 1628 2237 IL15RA - TRAF4 1197 2125 2073 IL17C - TRAF4 236 2464 19 IL17C - TRAF4 1538 914 1515 IL17REL - TRAF4 2422 381 2487 IL17REL - TRAF4 575 1394 320 RANKING OF IL FAMILY W.R.TTRAF6 RANKING OF TRAF6 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TRAF6 1 343 2237 IL1A - TRAF6 1637 455 2334 IL1B - TRAF6 224 143 2107 IL1B - TRAF6 861 1386 1342 IL1RAP - TRAF6 1875 1483 1433 IL1RAP - TRAF6 2219 1984 1766 IL1RN - TRAF6 107 706 988 IL1RN - TRAF6 1334 1067 1301 IL2RG - TRAF6 790 1706 1028 IL2RG - TRAF6 695 1717 1986 IL6ST - TRAF6 1508 928 930 IL6ST - TRAF6 54 762 1130 IL8 - TRAF6 2088 1883 2089 IL8 - TRAF6 2457 2139 1218 IL10RB - TRAF6 17 786 1211 IL10RB - TRAF6 303 1825 1709 IL15 - TRAF6 320 1692 2045 IL15 - TRAF6 2071 2475 1500 IL15RA - TRAF6 1560 303 2392 IL15RA - TRAF6 1688 1189 1344 IL17C - TRAF6 42 227 1457 IL17C - TRAF6 2469 2309 1503 IL17REL - TRAF6 2454 2517 412 IL17REL - TRAF6 124 2067 823 RANKING OF IL FAMILY W.R.TTRAFD1 RANKING OF TRAFD1 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TRAFD1 2408 1040 1579 IL1A - TRAFD1 2121 699 1587 IL1B - TRAFD1 1478 2046 1321 IL1B - TRAFD1 756 2435 571 IL1RAP - TRAFD1 491 1639 447 IL1RAP - TRAFD1 528 857 2043 IL1RN - TRAFD1 895 1149 266 IL1RN - TRAFD1 1033 848 1374 IL2RG - TRAFD1 1025 1948 43 IL2RG - TRAFD1 1243 492 1579 IL6ST - TRAFD1 1835 1824 809 IL6ST - TRAFD1 1064 868 699 IL8 - TRAFD1 1318 896 663 IL8 - TRAFD1 650 671 1088 IL10RB - TRAFD1 329 2371 355 IL10RB - TRAFD1 2403 556 800 IL15 - TRAFD1 1165 1934 769 IL15 - TRAFD1 339 623 634 IL15RA - TRAFD1 351 260 2385 IL15RA - TRAFD1 265 1369 386 IL17C - TRAFD1 1191 1389 1486 IL17C - TRAFD1 756 1068 1390 IL17REL - TRAFD1 704 2222 788 IL17REL - TRAFD1 370 640 137 Table 13: 2nd order combinatorial hypotheses between TRAF and IL 22 UNEXPLORED COMBINATORIAL HYPOTHESES IL w.r.t TRAF IL-1RAP/15RA/17REL TRAF3IP2 IL-6ST/17REL TRAF4 IL-8/17REL TRAF6 IL-6ST TRAFD1 TRAF w.r.t IL IL-1B/2RG/6ST/8/17REL TRAF3IP2 IL-10RB/15/15RA TRAF4 IL-1RAP/8/15/17C TRAF6 Table 14: 2nd order combinatorial hypotheses between IL and TRAF family. 23 RANKING INTERLEUKIN FAMILY VS STEAP4 FAMILY RANKING OF IL FAMILY W.R.TSTEAP4 RANKING OF STEAP4 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - STEAP4 422 482 992 IL1A - STEAP4 71 2358 2223 IL1B - STEAP4 423 814 982 IL1B - STEAP4 240 1570 1863 IL1RAP - STEAP4 2092 262 661 IL1RAP - STEAP4 1871 1898 2077 IL1RN - STEAP4 404 1602 370 IL1RN - STEAP4 195 2043 1763 IL2RG - STEAP4 1293 1458 1323 IL2RG - STEAP4 299 1562 1284 IL6ST - STEAP4 920 1641 2424 IL6ST - STEAP4 1374 504 1628 IL8 - STEAP4 2204 1987 1558 IL8 - STEAP4 794 1049 1615 IL10RB - STEAP4 2422 2310 1179 IL10RB - STEAP4 476 254 906 IL15 - STEAP4 700 1154 2320 IL15 - STEAP4 288 1965 2283 IL15RA - STEAP4 2277 1114 1528 IL15RA - STEAP4 1170 1334 1347 IL17C - STEAP4 433 2103 1889 IL17C - STEAP4 17 2426 1108 IL17REL - STEAP4 33 1965 2297 IL17REL - STEAP4 2439 715 100 Table 15: 2nd order combinatorial hypotheses between STEAP4 and IL 3.1.7. Interleukin - metalloreductase STEAP4 cross family analysis Ramadoss et al. [36] show that C/EBPαalso regulates hepatic expression of STEAP4 during feeding, whereas both C/EBPαand STAT3 regulate expression of steap4 in the presence of high levels of IL-6. Also, Tanaka et al. [37] show STEAP4 is a tumor necrosis factor alpha-induced protein that regulates IL-6, IL-8, and cell proliferation315 in synovium from patients with rheumatoid arthritis. These were found to be up regulated in CRC cells treated with ETC-1922159. Table 15 shows the interaction between the IL family and STEAP4. We found that IL-8/10RB/17C/17REL was up regulated w.r.t STEAP4. These are reflected in rankings of 2204 (laplace) and 1987 (linear) for IL8 - STEAP4; 2422 (laplace) and 2310 (linear) for IL10RB - STEAP4; 2103 (linear)320 and 1889 (rbf) for IL17C - STEAP4; and 1965 (linear) and 2297 (rbf) for IL17REL - STEAP4; Also STEAP4 was up regulated w.r.t IL-1A/1RAP/1RN/15. These are reflected in rankings of 2358 (linear) and 2223 (rbf) for IL1A - STEAP4; 1871 (laplace), 1898 (linear) and 2077 (rbf) for IL1RAP - STEAP4; 2043 (linear) and 1763 (rbf) for IL1RN - STEAP4; and 1965 (linear) and 2283 (rbf) for IL15 - STEAP4;325 Finally, table 16 shows the derived influences which can be represented graphically, with the following influences - •IL w.r.t STEAP4 with IL-8/10RB/17C/17REL <− STEAP4 •STEAP4 w.r.t IL with IL-1A/1RAP/1RN/15 −>STEAP4. 24 UNEXPLORED COMBINATORIAL HYPOTHESES IL w.r.t STEAP4 IL-8/10RB/17C/17REL STEAP4 STEAP4 w.r.t IL IL-1A/1RAP/1RN/15 STEAP4 Table 16: 2nd order combinatorial hypotheses between IL and STEAP4 family. 25 RANKING INTERLEUKIN FAMILY VS TNF FAMILY RANKING OF IL FAMILY W.R.TTNFAIP3 RANKING OF TNFAIP3 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TNFAIP3 2307 319 108 IL1A - TNFAIP3 78 51 2058 IL1B - TNFAIP3 495 98 339 IL1B - TNFAIP3 140 146 520 IL1RAP - TNFAIP3 30 2428 1376 IL1RAP - TNFAIP3 1802 1610 903 IL1RN - TNFAIP3 579 277 299 IL1RN - TNFAIP3 60 1610 1320 IL2RG - TNFAIP3 1705 330 125 IL2RG - TNFAIP3 1056 1608 2333 IL6ST - TNFAIP3 2068 2432 2282 IL6ST - TNFAIP3 1652 1470 1507 IL8 - TNFAIP3 1918 2255 1587 IL8 - TNFAIP3 2224 1717 118 IL10RB - TNFAIP3 1576 666 1377 IL10RB - TNFAIP3 1073 417 943 IL15 - TNFAIP3 732 254 273 IL15 - TNFAIP3 907 628 684 IL15RA - TNFAIP3 727 1547 1476 IL15RA - TNFAIP3 1340 445 1031 IL17C - TNFAIP3 1675 222 138 IL17C - TNFAIP3 1105 1887 866 IL17REL - TNFAIP3 2364 2503 2283 IL17REL - TNFAIP3 2040 1143 1486 RANKING OF IL FAMILY W.R.TTNFRSF1A RANKING OF TNFRSF1A W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TNFRSF1A 1556 2184 1375 IL1A - TNFRSF1A 2028 113 226 IL1B - TNFRSF1A 1621 1917 446 IL1B - TNFRSF1A 147 2027 2247 IL1RAP - TNFRSF1A 1236 2500 2293 IL1RAP - TNFRSF1A 1339 1003 2062 IL1RN - TNFRSF1A 411 1571 755 IL1RN - TNFRSF1A 1713 387 102 IL2RG - TNFRSF1A 565 2350 574 IL2RG - TNFRSF1A 1191 597 1479 IL6ST - TNFRSF1A 2221 1465 561 IL6ST - TNFRSF1A 1143 291 225 IL8 - TNFRSF1A 1536 750 304 IL8 - TNFRSF1A 1483 669 673 IL10RB - TNFRSF1A 620 35 1791 IL10RB - TNFRSF1A 230 1510 385 IL15 - TNFRSF1A 345 489 384 IL15 - TNFRSF1A 157 838 425 IL15RA - TNFRSF1A 442 1155 697 IL15RA - TNFRSF1A 682 322 1575 IL17C - TNFRSF1A 1113 284 149 IL17C - TNFRSF1A 5 169 122 IL17REL - TNFRSF1A 766 336 249 IL17REL - TNFRSF1A 1547 452 22 RANKING OF IL FAMILY W.R.TTNFRSF10A RANKING OF TNFRSF10A W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TNFRSF10A 366 73 48 IL1A - TNFRSF10A 1972 1805 2504 IL1B - TNFRSF10A 317 45 367 IL1B - TNFRSF10A 2375 2373 2320 IL1RAP - TNFRSF10A 2104 1342 2027 IL1RAP - TNFRSF10A 981 1665 2504 IL1RN - TNFRSF10A 1739 346 173 IL1RN - TNFRSF10A 1261 2287 2469 IL2RG - TNFRSF10A 645 1448 1009 IL2RG - TNFRSF10A 1244 2246 2467 IL6ST - TNFRSF10A 1307 823 1778 IL6ST - TNFRSF10A 2128 2320 1738 IL8 - TNFRSF10A 402 1615 1908 IL8 - TNFRSF10A 566 733 2117 IL10RB - TNFRSF10A 1243 689 2119 IL10RB - TNFRSF10A 389 532 723 IL15 - TNFRSF10A 321 1602 358 IL15 - TNFRSF10A 2414 2260 1705 IL15RA - TNFRSF10A 2126 2342 148 IL15RA - TNFRSF10A 2398 1970 2088 IL17C - TNFRSF10A 981 269 1027 IL17C - TNFRSF10A 1831 2025 1718 IL17REL - TNFRSF10A 2497 2470 2109 IL17REL - TNFRSF10A 1034 1482 2068 Table 22: 2nd order combinatorial hypotheses between TNF and IL IL-15RA was up regulated w.r.t TNFRSF10B. This is reflected in the rankings of 2330 (laplace) and 1932 (rbf) for IL15RA - TNFRSF10B; IL-15RA was up regulated w.r.t445 TNFRSF10D. This is reflected in the rankings of 2197 (laplace) and 2126 (rbf) for IL-15RA - TNFRSF10D; IL-8/15RA/17REL were up regulated w.r.t TNFRSF12A. These are reflected in the rankings of 1827 (linear) and 2355 (rbf) for IL8 - TNFRSF12A; 2138 (laplace), 2090 (linear) and 1981 (rbf) for IL15RA - TNFRSF12A; 2475 (laplace) and 2496 (rbf) for IL17REL - TNFRSF12A. IL-15RA was up regulated450 32 w.r.t TNFRSF14. This is reflected in the rankings of 2378 (laplace) and 1929 (rbf) for IL-15RA - TNFRSF14; IL-1B/1RAP/2RG were up regulated w.r.t TNFRSF21. These are reflected in the rankings of 1862 (laplace), 2164 (linear), 2305 (rbf) for IL1B - TNFRSF21; 1762 (linear) and 2163 (rbf) for IL1RAP - TNFRSF21; and 2297 (linear) and 2351 (rbf) for IL2RG - TNFRSF21; IL-1B/15RA/17C were up regulated w.r.t TN-455 FRSF10. These are reflected in the rankings of 2448 (linear) and 1993 (rbf) for IL1B - TNFSF10; 2163 (linear) and 2059 (rbf) for IL15RA - TNFSF10; and 2337 (linear) and 2431 (rbf) for IL17C - TNFSF10. IL-15RA/17C to be up regulated w.r.t TNFSF15. This is reflected in the rankings of 2222 (laplace) and 2328 (linear) for IL-17C - TNFSF15; and 2124 (laplace) and 2365 (rbf) for IL15RA - TNFSF15;460 On the right side, we found TNF was up regulated w.r.t IL-6ST/10RB. These are reflected in the rankings of 2410 (laplace) and 1901 (linear) for IL6ST - TNF; and 2065 (laplace), 2120 (linear) and 2296 (rbf) for IL10RB - TNF; TNFAIP1 was up regulated w.r.t IL-8/15RA. These are reflected in the rankings of 2293 (laplace) and 2126 (linear) for IL8 - TNFAIP1; and 2141 (linear) and 1853 (rbf) for IL15RA - TN-465 FAIP1; TNFRSF1A was up regulated w.r.t IL-1B. This is reflected in the rankings of 2027 (linear) and 2247 (rbf) for IL1B - TNFRSF1A; TNFRSF10A was up regulated w.r.t IL-1A/1B/1RN/2RG/6ST/15/15RA/17C. These are reflected in the rankings of 1972 (laplace), 1805 (linear) and 2504 (rbf) for IL1A - TNFRSF10A; 2375 (laplace), 2373 (linear) and 2320 (rbf) for IL1B - TNFRSF10A; 2287 (linear) and 2469 (rbf) for470 IL1RN - TNFRSF10A; 2246 (linear) and 2467 (rbf) for IL2RG - TNFRSF10A; 2128 (laplace) and 2320 (linear) for IL6ST - TNFRSF10A; 2414 (laplace) and 2260 (linear) for IL15 - TNFRSF10A; 2398 (laplace) and 1970 (linear) and 2088 (rbf) for IL15RA - TNFRSF10A; and 1831 (laplace) and 2025 (linear) for IL17C - TNFRSF10A; TNFRSF10B was up regulated w.r.t IL-1RN. This is reflected in the rankings of 2087475 (laplace) and 1966 (rbf) for IL1RN - TNFRSF10B; TNFRSF10D was up regulated w.r.t IL-1A/1B/2RG/6ST/10RB/15/17C/17REL. These are reflected in the rankings of 2415 (laplace), 2517 (linear) and 1894 (rbf) for IL1A - TNFRSF10D; 2513 (laplace), 2300 (linear) and 2430 (rbf) for IL1B - TNFRSF10D; 2514 (laplace), 2419 (linear) and 2043 (rbf) for IL2RG - TNFRSF10D; 2324 (laplace), 2515 (linear) for IL6ST - TN-480 FRSF10D; 1822 (laplace), 1959 (linear) for IL10RB - TNFRSF10D; 2490 (laplace), 2234 (linear) and 2019(rbf) for IL15 - TNFRSF10D; 2493 (laplace), 2062 (linear) and 2488 (rbf) for IL17C - TNFRSF10D; and 2514 (laplace) and 2452 (rbf) for IL17REL - TNFRSF10D. TNFRSF12A was up regulated w.r.t IL-16ST/17C. These are reflected in the rankings of 2213 (linear) and 2187 (rbf) for IL6ST - TNFRSF12A; and 1898 (lin-485 ear) and 2209 (rbf) for IL17C - TNFRSF12A; TNFRSF14 was up regulated w.r.t IL1A/1RN/2RG/6ST/8/15RA/17C. These are reflected in the rankings of 2061 (laplace) and 1969 (linear) for IL1A - TNFRSF14; 1898 (laplace) and 2414 (linear) for IL1RN - TNFRSF14; 2009 (laplace) and 1949 (linear) for IL2RG - TNFRSF14; 1923 (linear) and 2175 (rbf) for IL6ST - TNFRSF14; 1776 (laplace) and 2205 (rbf) for IL8490 - TNFRSF14; 2440 (laplace) and 2031 (linear) for IL15RA - TNFRSF14; and 1856 (laplace) and 1836 (linear) for IL17C - TNFRSF14. TNFRSF21 was up regulated w.r.t IL-17REL. This is reflected in the rankings of 1846 (laplace) and 2381 (rbf) for IL17REL - TNFRSF21; TNFRSF10 was up regulated w.r.t IL-10RB. This is reflected in the rankings 2252 (linear) and 1864 (rbf) of IL10RB - TNFSF10; TNFRSF15 was495 up regulated w.r.t IL-15. This is reflected in the rankings of 1922 (linear) and 1756 33 (rbf) for IL15 - TNFSF15. Finally, table 25 shows the derived influences which can be represented graphically, with the following influences - •IL w.r.t TNF with IL-1RAP/6ST/15RA < −TNF; IL-1B/2RG/15RA/17C <−TNFAIP1; IL-1RN/10RB <−TNFAIP2; IL-500 6ST/8/17REL <−TNFAIP3; IL-1RAP <−TNFRSF1A; IL-1RAP/15RA/17REL <−TNFRSF10A; IL-15RA <−TNFRSF10B; IL-15RA <−TNFRSF10D; IL8/15RA/17REL <−TNFRSF12A; IL-15RA <−TNFRSF14; IL-1B/1RAP/2RG <− TNFRSF21; IL-1B/15RA/17C <−TNFSF10 andIL-17C <−TNFSF15;and •TNF w.r.t IL with IL-6ST/10RB −>TNF; IL-8/15RA −>TNFAIP1; IL-1B −>TN-505 FRSF1A; IL-1A/1B/1RN/2RG/6ST/15/15RA/17C −>TNFRSF10A; IL-1RN −> TNFRSF10B; IL-1A/1B/2RG/6ST/10RB/15/17C/17REL −>TNFRSF10D; IL-6ST/17C −>TNFRSF12A; IL-1A/1RN/2RG/6ST/8/15RA/17C/17REL −>TNFRSF14; IL17REL −>TNFRSF14; IL10RB −>TNFSF10; and IL15 −>TNFSF15; 34 RANKING INTERLEUKIN FAMILY VS TNF FAMILY RANKING OF IL FAMILY W.R.TTNFRSF10B RANKING OF TNFRSF10B W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TNFRSF10B 771 190 110 IL1A - TNFRSF10B 294 1870 1471 IL1B - TNFRSF10B 2301 109 19 IL1B - TNFRSF10B 829 626 1465 IL1RAP - TNFRSF10B 752 2148 1579 IL1RAP - TNFRSF10B 2102 1685 405 IL1RN - TNFRSF10B 840 2005 443 IL1RN - TNFRSF10B 2087 1403 1966 IL2RG - TNFRSF10B 1868 1485 57 IL2RG - TNFRSF10B 1616 2134 1376 IL6ST - TNFRSF10B 788 1851 1038 IL6ST - TNFRSF10B 1149 510 1603 IL8 - TNFRSF10B 1494 1467 2312 IL8 - TNFRSF10B 1769 1763 196 IL10RB - TNFRSF10B 461 1770 1497 IL10RB - TNFRSF10B 1212 994 1542 IL15 - TNFRSF10B 360 1028 620 IL15 - TNFRSF10B 1712 815 2039 IL15RA - TNFRSF10B 2330 932 1932 IL15RA - TNFRSF10B 1640 1375 2210 IL17C - TNFRSF10B 557 1911 91 IL17C - TNFRSF10B 1594 969 1624 IL17REL - TNFRSF10B 457 1701 2422 IL17REL - TNFRSF10B 1074 2117 347 RANKING OF IL FAMILY W.R.TTNFRSF10D RANKING OF TNFRSF10D W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TNFRSF10D 143 625 21 IL1A - TNFRSF10D 2415 2517 1894 IL1B - TNFRSF10D 185 142 191 IL1B - TNFRSF10D 2513 2300 2430 IL1RAP - TNFRSF10D 1106 1750 1376 IL1RAP - TNFRSF10D 811 1241 1946 IL1RN - TNFRSF10D 881 520 337 IL1RN - TNFRSF10D 2512 1658 857 IL2RG - TNFRSF10D 713 413 905 IL2RG - TNFRSF10D 2514 2419 2043 IL6ST - TNFRSF10D 752 2009 1617 IL6ST - TNFRSF10D 2324 2515 460 IL8 - TNFRSF10D 1267 903 629 IL8 - TNFRSF10D 463 446 2468 IL10RB - TNFRSF10D 1072 1050 1031 IL10RB - TNFRSF10D 1822 1959 982 IL15 - TNFRSF10D 108 842 333 IL15 - TNFRSF10D 2490 2234 2019 IL15RA - TNFRSF10D 2197 943 2126 IL15RA - TNFRSF10D 1895 1048 24 IL17C - TNFRSF10D 11 268 7 IL17C - TNFRSF10D 2493 2062 2488 IL17REL - TNFRSF10D 54 638 278 IL17REL - TNFRSF10D 2514 100 2452 RANKING OF IL FAMILY W.R.TTNFRSF12A RANKING OF TNFRSF12A W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TNFRSF12A 52 2189 374 IL1A - TNFRSF12A 239 2080 1330 IL1B - TNFRSF12A 709 1592 1066 IL1B - TNFRSF12A 1422 516 1025 IL1RAP - TNFRSF12A 606 1030 1639 IL1RAP - TNFRSF12A 165 1595 1273 IL1RN - TNFRSF12A 122 1173 1182 IL1RN - TNFRSF12A 2176 529 1135 IL2RG - TNFRSF12A 206 1875 756 IL2RG - TNFRSF12A 1705 1060 2416 IL6ST - TNFRSF12A 2128 898 1092 IL6ST - TNFRSF12A 707 2213 2187 IL8 - TNFRSF12A 1132 1827 2355 IL8 - TNFRSF12A 461 1199 1587 IL10RB - TNFRSF12A 51 37 238 IL10RB - TNFRSF12A 852 781 910 IL15 - TNFRSF12A 281 1535 686 IL15 - TNFRSF12A 1984 1469 530 IL15RA - TNFRSF12A 2138 2090 1981 IL15RA - TNFRSF12A 1065 576 1568 IL17C - TNFRSF12A 326 2512 52 IL17C - TNFRSF12A 1497 1898 2209 IL17REL - TNFRSF12A 2475 587 2496 IL17REL - TNFRSF12A 148 1299 410 RANKING OF IL FAMILY W.R.TTNFRSF14 RANKING OF TNFRSF14 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TNFRSF14 208 29 683 IL1A - TNFRSF14 2061 1969 693 IL1B - TNFRSF14 70 664 924 IL1B - TNFRSF14 592 1647 1743 IL1RAP - TNFRSF14 1356 2249 756 IL1RAP - TNFRSF14 2103 1414 1691 IL1RN - TNFRSF14 1001 794 745 IL1RN - TNFRSF14 1898 2414 975 IL2RG - TNFRSF14 1619 1780 1158 IL2RG - TNFRSF14 2009 1949 1367 IL6ST - TNFRSF14 2248 221 619 IL6ST - TNFRSF14 1033 1923 2175 IL8 - TNFRSF14 517 299 1301 IL8 - TNFRSF14 1776 578 2205 IL10RB - TNFRSF14 1595 156 943 IL10RB - TNFRSF14 763 1457 834 IL15 - TNFRSF14 1265 550 1692 IL15 - TNFRSF14 2039 954 1230 IL15RA - TNFRSF14 2378 1929 1577 IL15RA - TNFRSF14 2440 2031 253 IL17C - TNFRSF14 11 40 605 IL17C - TNFRSF14 1856 1836 671 IL17REL - TNFRSF14 46 306 293 IL17REL - TNFRSF14 2312 72 1623 Table 23: 2nd order combinatorial hypotheses between IL and TNF 35 RANKING INTERLEUKIN FAMILY VS TNF FAMILY RANKING OF IL FAMILY W.R.TTNFRSF21 RANKING OF TNFRSF21 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TNFRSF21 904 2313 1127 IL1A - TNFRSF21 322 1745 688 IL1B - TNFRSF21 1862 2164 2305 IL1B - TNFRSF21 1336 157 829 IL1RAP - TNFRSF21 1446 1762 2163 IL1RAP - TNFRSF21 563 22 497 IL1RN - TNFRSF21 1593 2373 627 IL1RN - TNFRSF21 1626 1341 320 IL2RG - TNFRSF21 403 2297 2351 IL2RG - TNFRSF21 618 719 981 IL6ST - TNFRSF21 1372 1894 753 IL6ST - TNFRSF21 2019 1123 1143 IL8 - TNFRSF21 1204 1944 1585 IL8 - TNFRSF21 2493 999 1513 IL10RB - TNFRSF21 238 845 1081 IL10RB - TNFRSF21 2502 842 1641 IL15 - TNFRSF21 1591 1905 1740 IL15 - TNFRSF21 65 1459 96 IL15RA - TNFRSF21 421 1934 1269 IL15RA - TNFRSF21 98 1109 1259 IL17C - TNFRSF21 2130 1039 1676 IL17C - TNFRSF21 2272 1163 266 IL17REL - TNFRSF21 557 765 61 IL17REL - TNFRSF21 1846 704 2381 RANKING OF IL FAMILY W.R.TTNFRS10 RANKING OF TNFRS10 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TNFSF10 120 1575 2499 IL1A - TNFSF10 2369 1086 1034 IL1B - TNFSF10 972 2448 1993 IL1B - TNFSF10 2348 1544 1076 IL1RAP - TNFSF10 754 1045 2015 IL1RAP - TNFSF10 1613 2470 966 IL1RN - TNFSF10 740 1535 570 IL1RN - TNFSF10 1035 75 1074 IL2RG - TNFSF10 2272 1447 1285 IL2RG - TNFSF10 1032 882 1271 IL6ST - TNFSF10 1978 227 778 IL6ST - TNFSF10 1647 1602 2369 IL8 - TNFSF10 818 1702 791 IL8 - TNFSF10 1161 790 2265 IL10RB - TNFSF10 744 1146 2257 IL10RB - TNFSF10 1496 2252 1864 IL15 - TNFSF10 967 1382 1910 IL15 - TNFSF10 1400 1383 486 IL15RA - TNFSF10 346 2163 2059 IL15RA - TNFSF10 1458 790 1428 IL17C - TNFSF10 460 2337 2431 IL17C - TNFSF10 558 1004 942 IL17REL - TNFSF10 1728 145 989 IL17REL - TNFSF10 1664 718 250 RANKING OF IL FAMILY W.R.TTNFRS15 RANKING OF TNFRS15 W.R.TIL FAMILY laplace linear rbf laplace linear rbf IL1A - TNFSF15 1177 2494 979 IL1A - TNFSF15 1014 613 1449 IL1B - TNFSF15 1435 1529 1571 IL1B - TNFSF15 1898 1032 767 IL1RAP - TNFSF15 271 1665 2368 IL1RAP - TNFSF15 890 843 793 IL1RN - TNFSF15 2319 377 566 IL1RN - TNFSF15 414 1457 1704 IL2RG - TNFSF15 316 874 487 IL2RG - TNFSF15 2332 1362 1632 IL6ST - TNFSF15 1834 1004 1471 IL6ST - TNFSF15 771 1171 1445 IL8 - TNFSF15 1266 1571 1141 IL8 - TNFSF15 2422 515 966 IL10RB - TNFSF15 1488 326 1367 IL10RB - TNFSF15 1611 2041 1635 IL15 - TNFSF15 1356 1508 737 IL15 - TNFSF15 201 1922 1756 IL15RA - TNFSF15 2124 956 2365 IL15RA - TNFSF15 1551 668 864 IL17C - TNFSF15 2222 2328 954 IL17C - TNFSF15 2403 1049 1338 IL17REL - TNFSF15 1214 177 208 IL17REL - TNFSF15 513 1515 1943 Table 24: 2nd order combinatorial hypotheses between IL and TNF 36 UNEXPLORED COMBINATORIAL HYPOTHESES IL w.r.t TNF IL-1RAP/6ST/15RA TNF IL-1B/2RG/15RA/17C TNFAIP1 IL-1RN/10RB TNFAIP2 IL-6ST/8/17REL TNFAIP3 IL-1RAP TNFRSF1A IL-1RAP/15RA/17REL TNFRSF10A IL-15RA TNFRSF10B IL-15RA TNFRSF10D IL-8/15RA/17REL TNFRSF12A IL-15RA TNFRSF14 IL-1B/1RAP/2RG TNFRSF21 IL-1B/15RA/17C TNFSF10 IL-17C TNFSF15 TNF w.r.t IL IL-6ST/10RB TNF IL-8/15RA TNFAIP1 IL-1B TNFRSF1A IL-1A/1B/1RN/2RG/6ST/15/15RA/17C TNFRSF10A IL-1RN TNFRSF10B IL-1A/1B/2RG/6ST/10RB/15/17C/17REL TNFRSF10D IL-6ST/17C TNFRSF12A IL-1A/1RN/2RG/6ST/8/15RA/17C/17REL TNFRSF14 IL-17REL TNFRSF14 IL10RB TNFSF10 IL15 TNFSF15 Table 25: 2nd order combinatorial hypotheses between IL and TNF family. 37 Conclusion510 Presented here are a range of multiple synergistic Interleukin 2nd order combinations that were ranked via a search engine. Later, two way cross family analysis between components of these combinations were conducted. Via majority voting across the ranking methods, it was possible to find plausible unexplored synergistic combinations that might be prevalent in CRC cells after treatment with ETC-1922159 drug.515 The two-way cross family analysis also assists in deriving influences between components which serve as hypotheses for further tests. If found true, it paves way for biologists/oncologists to further investigate and understand the mechanism behind the synergy through wet experiments. Conflict of interest520 There are no conflicts to declare. Author’s contributions Concept, design, in silico implementation - SS. Analysis and interpretation of results - SS. Manuscript writing - SS. Manuscript revision - SS. 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