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

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Advances in Colorectal Cancer Therapy

Submitted:

05 September 2024

Posted:

18 September 2024

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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 regu- lated, individually. A recently developed search engine ranked combinations of Inter- leukin (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 κ B (NFκB), Potassium ion channel sub- family members (KCN), mucin (MUC), TP53, STAT, TNF receptor as- sociated factor (TRAF), STEAP4 metalloreductase, STEAP3 metalloreductase, ATP- binding cassette (ABC) transporters and tumor necrosis factor (TNF).
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Subject: Computer Science and Mathematics  -   Mathematical and Computational Biology

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In the unpublished preprint Sinha [1], a frame work of a search engine was developed which can rank combinations of factors (genes/proteins) in a signaling pathway.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 combinations 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 Interested readers are advised to go through unpublished preprints Sinha [1] and Sinha [2] for details regarding the search engine and the discoveries mentioned in there.

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]. Readers 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 ETC-1922159. 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.
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 learns 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_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 of 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. NF κ B-2/I - Interleukin Cross Family Analysis

Hörber et al. [5] show that the atypical inhibitor of NF- κ B, I κ B ζ , controls macrophage interleukin-10 expression. Yamazaki et al. [6] observe that stimulus-specific induction of a novel nuclear factor- κ B regulator, I κ B- 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 (NF κ B2) proto-oncogene/transcription factor in renal cell carcinoma lines. These studies and many others not indicated here, show the connection between Interleukin and NFkB-2 and NFkBI family. In CRC cells treated with 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 IL-15RA/17C to be up regulated w.r.t NFkB2. These are reflected in rankings of 1787 (rbf) and 1957 (rbf) IL15RA - NFkB2 and 2288 (linear) and 2018 (rbf) IL17C - NFkB2. IL-1RN/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. IL-1RAP/6ST/8/17REL to be up regulated w.r.t NFkB2. These are reflected in rankings 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 2098 (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) for 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; IL17REL < − NFkBIE; IL1A < − NFkBIZ; IL6ST < − NFkBIZ; IL15 < − NFkBIZ; and • NFkB-2/I w.r.t IL with IL10RB − > NFkB2; IL10RB − > NFKBIZ; IL17REL − > NFkBIZ;

3.1.2. Potassium Channel - Interleukin Cross Family Analysis

In 1986, Lee et al. [8] showed that increased voltage-gated potassium conductance 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 found 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 Table 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.t 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 2068 (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) for 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) and 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; 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 2060 (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 of 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 (laplace) and 2047 (rbf) for IL15 - KCNK6;
Finally, Table 5 shows the derived influences which can be represented graphically, with the following influences - • IL w.r.t KCN with 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; and • KCN w.r.t IL family with IL-1A/1B/15RA/17C − > KCND3; IL-1A/1RAP − > KCNH2; IL-1B/10RB − > KCNH8; IL-1A/6ST/8 − > KCNK1; IL-10RB − > KCNK5; and IL-1RAP/10RB/15 − > KCNK6;

3.1.3. Mucin - Interleukin Cross Family Analysis

Kerschner et al. [10] have observed that middle ear epithelial mucin production in response to interleukin-6 exposure in vitro. Chen et al. [11] observe that stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. Suppression of mucin 2 promotes interleukin-6 secretion and tumor growth in an orthotopic immune-competent colon cancer animal model was observed by Shan et al. [12]. Yokoigawa et al. [13] show enhanced production of interleukin 6 in peripheral blood monocytes stimulated with mucins secreted into the bloodstream. Gray et al. [14] show that interleukin-1 β -induced mucin production in human airway epithelium is mediated by cyclooxygenase-2, prostaglandin E2 receptors, and cyclic AMP-protein kinase A signaling. Finally, in colorectal cancer, Hsu et al. [15] mucin 2 silencing promotes metastasis through interleukin-6 signaling. In CRC cells treated with ETC-1922159, both were found to be up regulated. Table 6 and Table 7 show the rankings of IL family w.r.t MUC family on the left side and vice versa on the right side.
On the left side, we found IL-1B/17C to be up regulated with respect to MUC1. These are reflected in rankings of 2218 (laplace) 1757 (linear) for IL1B - MUC1; and 1841 (linear) and 2003 (rbf) for IL17C - MUC1; IL-1A/1B/1RN/2RG/15/17C were up regulated with respect to MUC3A. These are reflected in rankings of 2513 (laplace) and 2480 (linear) for IL1A - MUC3A; 1820 (laplace) and 2308 (linear) for IL1B - MUC3A; 2138 (laplace) and 2270 (linear) for IL1RN - MUC3A; 1816 (laplace), 2115 (linear) and 1900 (rbf) for IL2RG - MUC3A; 2391 (laplace) and 2288 (linear) for IL15 - MUC3A; and 2443 (laplace) and 2512 (linear) for IL17C - MUC3A; IL-1RN/6ST/15RA were up regulated with respect to MUC4. These are reflected in rankings of 2010 (laplace) and 1960 (rbf) for IL1RN - MUC4; 2204 (laplace) and 1765 (rbf) for IL6ST - MUC4; and 2190 (laplace), 1814 (linear) and 2061 (rbf) for IL15RA - MUC4; IL-1A/2RG/8/15/17C were up regulated with respect to MUC12. These are reflected in rankings of 1806 (laplace) and 2396 (rbf) for IL1A - MUC12; 2195 (laplace) and 2089 (rbf) for IL2RG - MUC12; 1814 (laplace) and 2497 (rbf) for IL8 - MUC12; 2408 (laplace) and 2340 (rbf) for IL15 - MUC12; and 2436 (laplace) and 2416 (rbf) for IL17C - MUC12; IL-15RA were up regulated with respect to MUC17. These are reflected in rankings of 2265 (laplace) and 2064 (linear) for IL15RA - MUC17. IL-1RAP/8/17REL were up regulated with respect to MUC20. These are reflected in rankings of 2025 (linear) and 2251 (rbf) for IL1RAP - MUC20; 1820 (laplace) and 2303 (rbf) for IL8 - MUC20; and 2121 (laplace) and 2267 (rbf) for IL17REL - MUC20.
On the left side, we found MUC1 to be up regulated with respect to IL-1B. These are reflected in rankings of 1847 (laplace) and 2049 (rbf) for IL1B - MUC1. MUC12 to be up regulated with respect to IL-1RN/2RG/6ST. These are reflected in rankings of 2505 (laplace) and 1891 (linear) for IL1RN - MUC12; 1913 (laplace) and 1833 (linear) for IL2RG - MUC12; and 2100 (laplace) and 1759 (linear) for IL6ST - MUC12. MUC13 to be up regulated with respect to IL-1RAP/15RA. These are reflected in rankings of 1887 (laplace) and 2263 (rbf) for IL1RAP - MUC13; and 2109 (laplace) and 2402 (rbf) for IL15RA - MUC13; MUC20 to be up regulated with respect to IL-1A/10RB/17C. These are reflected in rankings of 2218 (laplace) and 2260 (rbf) for IL1A - MUC20; 1883 (linear) and 1947 (rbf) for IL10RB - MUC20; and 2212 (laplace) and 1843 (linear) for IL17C - MUC20.
Finally, Table 8 shows the derived influences which can be represented graphically, with the following influences - • IL w.r.t MUC with IL-1B/17C < − MUC1; IL-1A/1B/1RN/2RG/15/17C and MUC3A; IL-1RN/6ST/15RA < − MUC4; IL-1A/2RG/8/15/17C < − MUC12; IL-15RA < − MUC17; and IL-1RAP/8/17REL < − MUC20; and • MUC w.r.t IL with IL-1B < − MUC1; IL-1RN/2RG/6ST < − MUC12; IL-1RAP/15RA < − MUC13; and IL-1A/10RB/17C < − MUC20;

3.1.4. Interleukin - TP53 Cross Family Analysis

In a new pathway connecting inflammation to cancer, Brighenti et al. [16] show that interleukin 6 downregulates p53 expression and activity by stimulating ribosome biogenesis. Tan et al. [17] show that loss of p53 attenuates the contribution of IL-6 deletion on suppressed tumor progression and extended survival in Kras-driven murine lung cancer. Pützer et al. [18] show that combination therapy with interleukin-2 and wild-type p53 expressed by adenoviral vectors potentiates tumor regression in a murine model of breast cancer. A critical role for p53 in the control of NF- κ B-dependent gene expression in TLR4-stimulated dendritic cells exposed to genistein has been shown by Dijsselbloem et al. [19]. The authors previously demonstrated that genistein suppresses TNF- α induced NF- κ B-dependent IL-6 gene expression in cancer cells by interfering with the mitogen- and stress-activated protein kinase 1 activation pathway. Schauer et al. [20] show that interleukin-1 β promotes ovarian tumorigenesis through a p53/NF- κ B-mediated inflammatory response in stromal fibroblasts. These findings indicate connection between IL and TP53 family. Table 9 shows the rankings of IL family w.r.t TP53 family on the left and vice versa on the right.
On the left side, we found IL-17REL to be up regulated with respect to TP53BP2. These are reflected in rankings of 1873 (linear) and 2403 (rbf). IL-15RA was up regulated with respect to TP53I3. These are reflected in rankings of 2069 (laplace), 2079 (linear) and 2228 (rbf) for IL15RA - TP53I3. IL-1RN/2RG/8/10RB/17REL was up regulated with respect to TP53INP1. These are reflected in rankings of 2482 (laplace) and 1911 (linear) for IL1RN - TP53INP1; 2152 (laplace) and 1798 (linear) for IL2RG - TP53INP1; 2388 (linear) and 2343 (rbf) for IL8 - TP53INP1; 2510 (laplace), 2293 (linear) for IL10RB - TP53INP1; and 2505 (linear) and 2509 (rbf) for IL17REL - TP53INP1.
On the right side, we found TP53BP2 to be up regulated with respect to IL-1A/1B/2RG/6ST/8/15/ 15RA. These are reflected in rankings of 2306 (linear) and 2483 (rbf) for IL1A - TP53BP2; 2003 (laplace) and 2317 (rbf) for IL1B - TP53BP2; 1842 (laplace), 1888 (linear) and 1791 (rbf) for IL2RG - TP53BP2; 1862 (laplace) and 2234 (rbf) for IL6ST - TP53BP2; 2356 (laplace), 2336 (linear) for IL8 - TP53BP2; 2029 (linear) and 1896 (rbf) for IL15 - TP53BP2; 2086 (laplace), 2287 (linear) and 2198 (rbf) for IL15RA - TP53BP2; TP53I3 was up regulated with respect to IL-17REL. This is reflected in rankings of 2268 (laplace) and 2220 (rbf) for IL17REL - TP53I3. TP53INP1 was up regulated with respect to IL2RG. This is reflected in rankings of 2063 (laplace) and 1864 (linear) and 1956 (rbf) IL2RG - TP53INP1. TP53INP2 was up regulated with respect to IL6ST. This is reflected in rankings of 2512 (laplace) and 1952 (linear).
Finally, Table 10 shows the derived influences which can be represented graphically, with the following influences - • IL w.r.t TP53 with IL17REL < − TP53BP2; IL15RA < − TP53I3; IL-1RN/2RG/8/10RB/17REL < − TP53INP1; and • TP53 w.r.t IL with IL-1A/1B/2RG/6ST/8/15/15RA − > TP53BP2; IL17REL − > TP53I3; IL2RG − > TP53INP1; and IL6ST − > TP53INP2.

3.1.5. Interleukin - STAT Cross Family Analysis

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-signaling 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 Kurgonaite 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/EBP β through 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 synthetic 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 and 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/17REL 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.
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) 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 1760 (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 w.r.t IL with IL-1RN/2RG − > STAT2; IL-1A/1RN/2RG/6ST/15 − > STAT3 and IL-2RG/8/17C − > STAT5A;

3.1.6. Interleukin - TRAF Cross Family Analysis

Greene and O’Neill [30] show that interleukin-1 receptor-associated kinase and TRAF-6 mediate the transcriptional regulation of interleukin-2 by interleukin-1 via NF κ B but unlike interleukin-1 are unable to stabilise interleukin-2 mRNA. Cao et al. [31] 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- κ B in response to 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 found 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 - 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; 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 2359 (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; 2408 (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;
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; IL-10RB/15/15RA − > TRAF4 and IL-1RAP/8/15/17C − > TRAF6.

3.1.7. Interleukin - Metalloreductase STEAP4 Cross Family Analysis

Ramadoss et al. [36] show that C/EBP α also regulates hepatic expression of STEAP4 during feeding, whereas both C/EBP α and 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 proliferation 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) 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;
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.

3.1.8. Interleukin - Metalloreductase STEAP3 Cross Family Analysis

Based on the interactions of STEAP4 and interleukin, we also generated rankings for STEAP3 and interleukin family. It was found that STEAP3 and interleukin family were down regulated. Table 17 shows the rankings of IL family w.r.t STEAP3 and vice versa. We found IL-1RL2/17D/17RB/17RD/33/F2/F3.AS1 to be down regulated w.r.t STEAP3. These are reflected in rankings of 619 (laplace) and 1471 (linear) for IL1RL2 - STEAP3; 1338 (laplace), 1275 (linear) and 458 (rbf) for IL17D - STEAP3; 1101 (laplace) and 239 (rbf) for IL17RB - STEAP3; 1323 (laplace) and 810 (linear) for IL17RD - STEAP3; 1589 (laplace) and 781 (linear) and 1210 (rbf) for IL33 - STEAP3; 1571 (laplace) and 811 (linear) and 579 (rbf) for ILF2 - STEAP3; and 947 (laplace) and 926 (rbf) for ILF3.AS1 - STEAP3. STEAP3 to be down regulated w.r.t IL-1RL2/17D/17RB/33/F3/F3.AS1. These are reflected in rankings of 835 (laplace) and 1733 (rbf) for IL1RL2 - STEAP3; 596 (laplace) and 705 (linear) for IL17D - STEAP3; 208 (laplace) and 404 (rbf) for IL17RB - STEAP3; 1070 (laplace) and 57 (linear) for IL33 - STEAP3; 121 (laplace) and 926 (rbf) for ILF3 - STEAP3 and 1592 (laplace), 678 (linear) and 1094 (rbf) for ILF3.AS1 - STEAP3. Finally, Table 18 shows the derived influences which can be represented graphically, with the following influences - • IL w.r.t STEAP3 with IL-1RL2/17D/17RB/17RD/33/F2/F3.AS1 < − STEAP3; and • STEAP3 w.r.t IL with IL-1RL2/17D/17RB/33/F3/F3.AS1 − > STEAP3.

3.1.9. Interleukin - ATP-Binding Cassette Transporters

Haskó et al. [38] show that the inhibitors of ATP-binding cassette transporters suppress interleukin-12 p40 production and major histocompatibility complex II up-regulation in macrophages. Marty et al. [39] observe that ATP binding cassette transporter ABC1 is required for the release of interleukin-1 β by P2X7-stimulated and lipopolysaccharide-primed mouse Schwann cells. Hamon et al. [40] observe that interleukin-1 β secretion is impaired by inhibitors of the ATP binding cassette transporter, ABC1. Lottaz et al. [41] show that inhibition of ATP-binding cassette transporter downregulates interleukin-1 β -mediated autocrine activation of human dermal fibroblasts. These findings indicate the interaction of ABC transporters with Interleukin family. In CRC cells, treated with ETC-1922159 these were found to be down regulated. Table 19 shows rankings of IL family with respect to a few ABC members on the left and vice versa on the right.
On the left we found IL-1RB/33/F2/F3 were down regulated w.r.t ABCA2. These are reflected in rankings of 1404 (linear) and 1727 (rbf) for IL17RB - ABCA2; 1076 (laplace), 1707 (linear) for IL33 - ABCA2; 944 (laplace) and 1054 (linear) for ILF2 - ABCA2; 1380 (laplace), 1369 (linear) and 1702 (rbf) for ILF3 - ABCA2; IL-1RL2/17D/17RD/33/F2/F3.AS1 were up regulated w.r.t ABCE1. These are reflected in rankings of 906 (laplace) and 1403 (linear) for IL1RL2 - ABCE1; 1531 (laplace), 636 (linear) and 753 (rbf) for IL17D - ABCE1; 1030 (laplace), 1332 (linear) and 1565 (rbf) for IL17RD - ABCE1; 1649 (laplace), 719 (linear) and 937 (rbf) for IL33 - ABCE1; 20 (laplace), 310 (linear) and 560 (rbf) for ILF2 - ABCE1; and 1154 (laplace) and 786 (rbf) for ILF3.AS1 - ABCE1. IL-17RB/17RD/F3 were up regulated w.r.t ABCF2. These are reflected in rankings of 509 (laplace) and 1294 (laplace) for IL17RB - ABCF2; 610 (laplace) and 1084 (rbf) for IL17RD - ABCF2; and 812 (laplace), 1686 (laplace) and 1080 (rbf) for ILF3 - ABCF2.
On the right, we found ABCA2 were up regulated w.r.t IL-17D/17RD/33/F2. These are reflected in rankings of 540 (laplace), 227 (linear) and 1006 (rbf) for IL17D - ABCA2; 1717 (laplace), 1671 (linear) and 517 (rbf) for IL17RD - ABCA2; 1507 (laplace), 497 (linear) and 743 (rbf) for IL33 - ABCA2; and 831 (laplace), 822 (linear) and 752 (rbf) for ILF2 - ABCA2; ABCE1 were up regulated w.r.t IL-1RL2/17D/17RB/17RD. These are reflected in rankings of 525 (laplace) and 723 (rbf) for IL1RL2 - ABCE1; 1432 (laplace) and 1401 (rbf) for IL17D - ABCE1; 1090 (laplace) and 263 (rbf) for IL17RB - ABCE1; and 1523 (laplace) and 727 (linear) for IL17RD - ABCE1; ABCF2 were up regulated w.r.t IL-1RL2/17D/17RB/17RD/33/F2/F3/F3.AS1. These are reflected in rankings of 818 (rbf) and 1274 (rbf) for IL1RL2 - ABCF2; 796 (laplace) and 568 (rbf) for IL17D - ABCF2; 1271 (laplace), 621 (linear) and 1631 (rbf) for IL17RB - ABCF2; 957 (laplace) and 1431 (rbf) for IL17RD - ABCF2; 421 (laplace) and 252 (rbf) for IL33 - ABCF2; 683 (laplace) and 529 (rbf) for ILF2 - ABCF2; 1243 (laplace), 585 (linear) and 1452 (rbf) for ILF3 - ABCF2 and 1169 (linear) and 862 (rbf) for ILF3.AS1 - ABCF2.
Finally, Table 20 shows the derived influences which can be represented graphically, with the following influences - • IL w.r.t ABC with IL-1RB/33/F2/F3 < − ABCA2; IL-1RL2/17D/17RD/33/F2/ F3.AS1 < − ABCE1 and IL-17RB/17RD/F3 < − ABCF2. • ABC w.r.t IL with IL-17D/17RD/33/F2 − > ABCA2; IL-1RL2/17D/17RB/17RD − > ABCE1 and IL-1RL2/17D/17RB/17RD/33/F2/F3/F3.AS1 − > ABCF2.

3.1.10. Interleukin - TNF Cross Family Analysis

Neta et al. [42] study the relationship of TNF to interleukins way back in 1992. The review by Rieckmann et al. [43] studies role of TNF- α and IL-6 in normal and pathophysiological conditions of B-cell function. Bethea et al. [44] demonstrate that IL-1 β induces TNF- α gene expression in CH235-MG cells in a protein kinase C-dependent manner. Tumor necrosis factor (TNF)- α and interleukin (IL)-1 β down-regulate intercellular adhesion molecule (ICAM)-2 expression on the endothelium as shown by McLaughlin et al. [45]. Zhai et al. [46] suggest that serum levels of tumor necrosis factor- α receptors and interleukin 6 (IL-6) are associated with the fibrotic process of coal workers’ pneumoconiosis (CWP) and serum cytokine levels may be correlated with the severity of CWP. However, in arthritic conditions, Koenders et al. [47] show that Interleukin-17 acts independently of TNF- α . Serum interleukin-6 (IL-6), IL-10, tumor necrosis factor (TNF) alpha, soluble type II TNF receptor, and transforming growth factor beta levels in human immunodeficiency virus type 1-infected individuals with Mycobacterium avium complex disease have been studied by Havlir et al. [48]. Tissi et al. [49] study the role of tumor necrosis factor alpha, interleukin-1 β , and interleukin-6 in a mouse model of group B streptococcal arthritis. They conclude that their results account for a strong involvement of IL-1 β and IL-6, but not of TNF- α , in the pathogenesis of GBS arthritis. Ismail et al. [50] study the role of tumor necrosis factor alpha (TNF- α ) and interleukin-10 in the pathogenesis of severe murine monocytotropic ehrlichiosis. Their data suggest that the balance between TNF- α and IL-10 produced by either macrophages or T cells in response to infection with Ehrlichia may modulate the induction of apoptosis during the infection. Yap et al. [51] observe that Tumor necrosis factor (TNF) inhibits interleukin (IL)-1 and/or IL-6 stimulated synthesis of C-reactive protein (CRP) and serum amyloid A (SAA) in primary cultures of human hepatocytes. These findings suggest interactive role of IL and TNF family in a synergistic way. In CRC cells treated with ETC-1922159, both were found to be up regulated. The search engine assigned high valued numerical ranks to 2nd order combinations of IL and TNF family members. These are tabulated in Table 21, Table 22, Table 23 and Table 24. The left side contains rankings of IL w.r.t TNF family and the right side contains rankings of TNF family w.r.t IL.
On the left side, we found IL-1RAP/6ST/15RA to be up regulated w.r.t TNF. These are reflected in the rankings of 1995 (linear) and 2255 (rbf) for IL1RAP - TNF; 2374 (laplace), 2037 (linear) and 2003 (rbf) for IL6ST - TNF; 2341 (laplace), 1843 (linear) and 2195 (rbf) for IL15RA - TNF; IL-1B/2RG/15RA/17C were up regulated w.r.t TNFAIP1. These are reflected in the rankings of 2398 (laplace) and 2449 (rbf) for IL1B - TNFAIP1; 1791 (laplace) and 2482 (rbf) for IL2RG - TNFAIP1; 1860 (laplace) and 1979 (linear) for IL15RA - TNFAIP1; 2382 (laplace) and 2446 (rbf) for IL17C - TNFAIP1. IL-1RN/10RB were up regulated w.r.t TNFAIP2. These are reflected in the rankings of 1769 (laplace) and 2475 (rbf) for IL1RN - TNFAIP2; and 2319 (laplace) and 2497 (rbf) for IL10RB - TNFAIP2; IL-6ST/8/17REL were up regulated w.r.t TNFAIP3. These are reflected in the rankings of 2068 (laplace), 2432 (linear) and 2282 (rbf) for IL6ST - TNFAIP3; 1918 (laplace) and 2255 (linear) for IL8 - TNFAIP3; and 2364 (laplace), 2503 (linear) and 2283 (rbf) for IL17REL - TNFAIP3; IL-1RAP was up regulated w.r.t TNFRSF1A. This is reflected in the rankings of 2500 (linear) and 2293 (rbf) for IL1RAP - TNFRSF1A; IL-1RAP/15RA/17REL were up regulated w.r.t TNFRSF10A. These are reflected in the rankings of 2104 (laplace) and 2027 (rbf) for IL1RAP - TNFRSF10A; 2126 (laplace), 2342 (linear) for IL15RA - TNFRSF10A; 2497 (laplace), 2470 (linear) and 2109 (rbf) for IL17REL - TNFRSF10A; 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.t 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 regulated 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 TNFRSF10. 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;
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 - TNFAIP1; 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) for 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 2087 (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 - TNFRSF10D; 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 (linear) and 2209 (rbf) for IL17C - TNFRSF12A; TNFRSF14 was up regulated w.r.t IL-1A/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 IL8 - 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 was up regulated w.r.t IL-15. This is reflected in the rankings of 1922 (linear) and 1756 (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-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 andIL-17C < − TNFSF15;and • TNF w.r.t IL with 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; and IL15 − > TNFSF15;

Conclusion

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. 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.

Source of Data

Data used in this research work was released in a publication in Madan et al. [52]. The ETC-1922159 was released in Singapore in July 2015 under the flagship of the Agency for Science, Technology and Research (A*STAR) and Duke-National University of Singapore Graduate Medical School (Duke-NUS).

Author Contributions

Concept, design, in silico implementation - SS. Analysis and interpretation of results - SS. Manuscript writing - SS. Manuscript revision - SS. Approval of manuscript - SS.

Acknowledgments

Special thanks to Mrs. Rita Sinha and Mr. Prabhat Sinha for supporting the author financially, without which this work could not have been made possible.

Conflicts of Interest

There are no conflicts to declare.

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Table 1. 2nd order combinatorial hypotheses between NFkB-2/I and IL.
Table 1. 2nd order combinatorial hypotheses between NFkB-2/I and IL.
Ranking Interleukin family vs NFkB-2 family
Ranking of IL family w.r.t NFkB-2 Ranking of NFkB-2/I w.r.t IL 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.t NFkBI-A Ranking of NFkB-2/I w.r.t IL 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.t NFkBI-E Ranking of NFkBI-E w.r.t IL 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.t NFkBI-Z Ranking of NFkBI-Z w.r.t IL 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 2. 2nd order combinatorial hypotheses between IL and NFkB-2/I family.
Table 2. 2nd order combinatorial hypotheses between IL and NFkB-2/I family.
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 3. 2nd order combinatorial hypotheses between KCN and IL.
Table 3. 2nd order combinatorial hypotheses between KCN and IL.
Ranking Interleukin family vs KCN family
Ranking of IL family w.r.t KCND3 Ranking of KCND3 w.r.t IL 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.t KCNH2 Ranking of KCNH2 w.r.t IL 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.t KCNH8 Ranking of KCNH8 w.r.t IL 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 4. 2nd order combinatorial hypotheses between KCN and IL.
Table 4. 2nd order combinatorial hypotheses between KCN and IL.
Ranking Interleukin family vs KCN family
Ranking of IL family w.r.t KCNK1 Ranking of KCNK1 w.r.t IL 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.t KCNK5 Ranking of KCNK5 w.r.t IL 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.t KCNK6 Ranking of KCNK6 w.r.t IL 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 5. 2nd order combinatorial hypotheses between IL family w.r.t KCN family.
Table 5. 2nd order combinatorial hypotheses between IL family w.r.t KCN family.
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 6. 2nd order combinatorial hypotheses between MUC and IL.
Table 6. 2nd order combinatorial hypotheses between MUC and IL.
Ranking Interleukin family vs MUC family
Ranking of IL family w.r.t MUC1 Ranking of MUC1 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - MUC1 1961 1711 107 IL1A - MUC1 111 879 535
IL1B - MUC1 2218 1757 228 IL1B - MUC1 1847 520 2049
IL1RAP - MUC1 837 604 146 IL1RAP - MUC1 1968 589 439
IL1RN - MUC1 1084 918 1859 IL1RN - MUC1 1752 353 507
IL2RG - MUC1 1872 272 1281 IL2RG - MUC1 1769 1009 285
IL6ST - MUC1 2415 1115 1633 IL6ST - MUC1 296 801 245
IL8 - MUC1 1276 544 1055 IL8 - MUC1 2079 1320 82
IL10RB - MUC1 291 1638 1710 IL10RB - MUC1 973 1691 924
IL15 - MUC1 212 1003 1060 IL15 - MUC1 160 205 942
IL15RA - MUC1 213 1346 1067 IL15RA - MUC1 1127 1057 1521
IL17C - MUC1 1215 1841 2003 IL17C - MUC1 3 236 7
IL17REL - MUC1 19 44 2069 IL17REL - MUC1 1142 541 1464
Ranking of IL family w.r.t MUC3A Ranking of MUC3A w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - MUC3A 2513 2480 194 IL1A - MUC3A 1426 1017 1484
IL1B - MUC3A 1820 2308 1086 IL1B - MUC3A 816 1157 908
IL1RAP - MUC3A 753 1270 526 IL1RAP - MUC3A 1403 1402 102
IL1RN - MUC3A 2138 2270 313 IL1RN - MUC3A 1123 360 1333
IL2RG - MUC3A 1816 2115 1900 IL2RG - MUC3A 480 1560 514
IL6ST - MUC3A 283 1126 1229 IL6ST - MUC3A 1601 908 889
IL8 - MUC3A 356 760 1517 IL8 - MUC3A 2350 587 80
IL10RB - MUC3A 1401 729 157 IL10RB - MUC3A 520 458 2324
IL15 - MUC3A 850 2391 2288 IL15 - MUC3A 1385 1351 959
IL15RA - MUC3A 1304 1949 959 IL15RA - MUC3A 1538 1685 584
IL17C - MUC3A 2443 2512 647 IL17C - MUC3A 2153 623 1349
IL17REL - MUC3A 200 243 2048 IL17REL - MUC3A 1274 1250 1387
Ranking of IL family w.r.t MUC4 Ranking of MUC4 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - MUC4 1268 489 112 IL1A - MUC4 42 1449 331
IL1B - MUC4 779 1142 393 IL1B - MUC4 780 301 393
IL1RAP - MUC4 1672 1203 926 IL1RAP - MUC4 460 358 883
IL1RN - MUC4 2010 438 1960 IL1RN - MUC4 1681 1164 51
IL2RG - MUC4 161 292 36 IL2RG - MUC4 581 659 1056
IL6ST - MUC4 2204 1116 1765 IL6ST - MUC4 977 1555 873
IL8 - MUC4 619 741 1030 IL8 - MUC4 222 1341 1552
IL10RB - MUC4 1818 1343 599 IL10RB - MUC4 87 1511 95
IL15 - MUC4 434 1268 602 IL15 - MUC4 440 806 276
IL15RA - MUC4 2190 1814 2061 IL15RA - MUC4 427 1145 305
IL17C - MUC4 255 60 558 IL17C - MUC4 167 152 159
IL17REL - MUC4 222 482 52 IL17REL - MUC4 2266 419 160
Ranking of IL family w.r.t MUC12 Ranking of MUC12 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - MUC12 1806 166 2396 IL1A - MUC12 706 84 570
IL1B - MUC12 1004 113 2086 IL1B - MUC12 1352 167 445
IL1RAP - MUC12 1906 1588 517 IL1RAP - MUC12 52 272 1955
IL1RN - MUC12 2209 669 235 IL1RN - MUC12 2505 1891 567
IL2RG - MUC12 2195 751 2089 IL2RG - MUC12 1913 1833 939
IL6ST - MUC12 1115 1522 1031 IL6ST - MUC12 2100 1759 1508
IL8 - MUC12 1814 1554 2497 IL8 - MUC12 439 121 1635
IL10RB - MUC12 2467 1114 1044 IL10RB - MUC12 381 1863 12
IL15 - MUC12 2408 192 2340 IL15 - MUC12 2400 1307 1408
IL15RA - MUC12 612 1636 203 IL15RA - MUC12 137 127 468
IL17C - MUC12 2436 484 2416 IL17C - MUC12 411 182 283
IL17REL - MUC12 2421 331 611 IL17REL - MUC12 1452 678 651
Table 7. 2nd order combinatorial hypotheses between MUC and IL.
Table 7. 2nd order combinatorial hypotheses between MUC and IL.
Ranking Interleukin family vs MUC family contd.
Ranking of IL family w.r.t MUC13 Ranking of MUC13 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - MUC13 655 2323 826 IL1A - MUC13 1176 148 803
IL1B - MUC13 2250 298 185 IL1B - MUC13 833 30 8
IL1RAP - MUC13 386 490 360 IL1RAP - MUC13 1887 1142 2263
IL1RN - MUC13 904 1614 698 IL1RN - MUC13 1749 1607 313
IL2RG - MUC13 1043 59 27 IL2RG - MUC13 434 852 1140
IL6ST - MUC13 635 1774 730 IL6ST - MUC13 1901 535 163
IL8 - MUC13 225 510 1130 IL8 - MUC13 2328 722 555
IL10RB - MUC13 944 491 1631 IL10RB - MUC13 1459 1841 342
IL15 - MUC13 1773 609 1047 IL15 - MUC13 315 465 302
IL15RA - MUC13 1884 1360 1067 IL15RA - MUC13 2109 158 2402
IL17C - MUC13 562 106 149 IL17C - MUC13 73 4 84
IL17REL - MUC13 1808 83 59 IL17REL - MUC13 694 676 586
Ranking of IL family w.r.t MUC17 Ranking of MUC17 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - MUC17 1573 2431 1622 IL1A - MUC17 881 311 254
IL1B - MUC17 1122 514 1035 IL1B - MUC17 676 1243 174
IL1RAP - MUC17 1634 1148 1469 IL1RAP - MUC17 136 369 2512
IL1RN - MUC17 38 260 911 IL1RN - MUC17 361 22 690
IL2RG - MUC17 754 218 403 IL2RG - MUC17 1379 530 177
IL6ST - MUC17 1616 554 1381 IL6ST - MUC17 1782 668 270
IL8 - MUC17 241 583 402 IL8 - MUC17 1612 436 1984
IL10RB - MUC17 401 464 51 IL10RB - MUC17 1707 1305 1857
IL15 - MUC17 307 438 878 IL15 - MUC17 466 366 596
IL15RA - MUC17 2265 2064 1458 IL15RA - MUC17 63 376 849
IL17C - MUC17 1045 581 2291 IL17C - MUC17 1530 285 1449
IL17REL - MUC17 656 657 456 IL17REL - MUC17 380 580 1306
Ranking of IL family w.r.t MUC20 Ranking of MUC20 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - MUC20 103 1729 18 IL1A - MUC20 2218 1499 2260
IL1B - MUC20 85 1810 30 IL1B - MUC20 1313 1719 735
IL1RAP - MUC20 974 2025 2251 IL1RAP - MUC20 1784 859 1705
IL1RN - MUC20 1176 2264 246 IL1RN - MUC20 1265 726 823
IL2RG - MUC20 405 2168 335 IL2RG - MUC20 2152 165 1400
IL6ST - MUC20 1475 1093 2233 IL6ST - MUC20 1743 203 1643
IL8 - MUC20 1820 538 2303 IL8 - MUC20 1875 883 488
IL10RB - MUC20 394 1884 312 IL10RB - MUC20 889 1883 1947
IL15 - MUC20 244 2241 166 IL15 - MUC20 1412 2057 1669
IL15RA - MUC20 589 1406 1406 IL15RA - MUC20 1450 1902 1570
IL17C - MUC20 228 2278 46 IL17C - MUC20 2212 1843 255
IL17REL - MUC20 2121 962 2267 IL17REL - MUC20 1130 1000 1868
Table 8. 2nd order combinatorial hypotheses between IL and NFkB-2/I family.
Table 8. 2nd order combinatorial hypotheses between IL and NFkB-2/I family.
Unexplored combinatorial hypotheses
IL w.r.t MUC
IL-1B/17C MUC1
IL-1A/1B/1RN/2RG/15/17C MUC3A
IL-1RN/6ST/15RA MUC4
IL-1A/2RG/8/15/17C MUC12
IL-15RA MUC17
IL-1RAP/8/17REL MUC20
MUC w.r.t IL
IL-1B MUC1
IL-1RN/2RG/6ST MUC12
IL-1RAP/15RA MUC13
IL-1A/10RB/17C MUC20
Table 9. 2nd order combinatorial hypotheses between TP53 and IL.
Table 9. 2nd order combinatorial hypotheses between TP53 and IL.
Ranking Interleukin family vs TP53 family
Ranking of IL family w.r.t TP53BP2 Ranking of TP53BP2 w.r.t IL 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.t TP53I3 Ranking of TP53I3 w.r.t IL 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.t TP53INP1 Ranking of TP53INP1 w.r.t IL 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.t TP53INP2 Ranking of TP53INP2 w.r.t IL 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 10. 2nd order combinatorial hypotheses between IL and NFkB-2/I family.
Table 10. 2nd order combinatorial hypotheses between IL and NFkB-2/I family.
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 11. 2nd order combinatorial hypotheses between STAT and IL.
Table 11. 2nd order combinatorial hypotheses between STAT and IL.
Ranking Interleukin family vs STAT family
Ranking of IL family w.r.t STAT2 Ranking of STAT2 w.r.t IL 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.t STAT3 Ranking of STAT3 w.r.t IL 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.t STAT5A Ranking of STAT5A w.r.t IL 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 12. 2nd order combinatorial hypotheses between IL and STAT family.
Table 12. 2nd order combinatorial hypotheses between IL and STAT family.
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 13. 2nd order combinatorial hypotheses between TRAF and IL.
Table 13. 2nd order combinatorial hypotheses between TRAF and IL.
Ranking Interleukin family vs TRAF family
Ranking of IL family w.r.t TRAF3IP2 Ranking of TRAF3IP2 w.r.t IL 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.t TRAF4 Ranking of TRAF4 w.r.t IL 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.t TRAF6 Ranking of TRAF6 w.r.t IL 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.t TRAFD1 Ranking of TRAFD1 w.r.t IL 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 14. 2nd order combinatorial hypotheses between IL and TRAF family.
Table 14. 2nd order combinatorial hypotheses between IL and TRAF family.
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 15. 2nd order combinatorial hypotheses between STEAP4 and IL.
Table 15. 2nd order combinatorial hypotheses between STEAP4 and IL.
Ranking Interleukin family vs STEAP4 family
Ranking of IL family w.r.t STEAP4 Ranking of STEAP4 w.r.t IL 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 16. 2nd order combinatorial hypotheses between IL and STEAP4 family.
Table 16. 2nd order combinatorial hypotheses between IL and STEAP4 family.
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 17. 2nd order combinatorial hypotheses between STEAP3 and IL.
Table 17. 2nd order combinatorial hypotheses between STEAP3 and IL.
Ranking Interleukin family vs STEAP3 family
Ranking of IL family w.r.t STEAP3 Ranking of STEAP3 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1RL2 - STEAP3 619 1471 2246 IL1RL2 - STEAP3 835 2234 1733
IL17D - STEAP3 1338 1275 458 IL17D - STEAP3 596 705 2273
IL17RB - STEAP3 1101 2302 239 IL17RB - STEAP3 208 2462 404
IL17RD - STEAP3 1323 810 1834 IL17RD - STEAP3 2352 589 2233
IL33 - STEAP3 1589 781 1210 IL33 - STEAP3 1070 57 2098
ILF2 - STEAP3 1571 811 579 ILF2 - STEAP3 1986 1029 2474
ILF3 - STEAP3 261 1866 1953 ILF3 - STEAP3 121 2314 926
ILF3.AS1 - STEAP3 947 2255 926 ILF3.AS1 - STEAP3 1592 678 1094
Table 18. 2nd order combinatorial hypotheses between IL and STEAP3 family.
Table 18. 2nd order combinatorial hypotheses between IL and STEAP3 family.
Unexplored combinatorial hypotheses
IL w.r.t STEAP3
IL-1RL2/17D/17RB/17RD/33/F2/F3.AS1 - STEAP3
STEAP3 w.r.t IL
IL-1RL2/17D/17RB/33/F3/F3.AS1 - STEAP3
Table 19. 2nd order combinatorial hypotheses between ABC and IL.
Table 19. 2nd order combinatorial hypotheses between ABC and IL.
Ranking Interleukin family vs ABC family
Ranking of IL family w.r.t ABCA2 Ranking of ABCA2 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1RL2 - ABCA2 2055 2097 405 IL1RL2 - ABCA2 2022 2490 1234
IL17D - ABCA2 1778 2160 1120 IL17D - ABCA2 540 227 1006
IL17RB - ABCA2 2419 1404 1727 IL17RB - ABCA2 2146 1543 1991
IL17RD - ABCA2 2202 1799 358 IL17RD - ABCA2 1717 1671 517
IL33 - ABCA2 1076 1707 1854 IL33 - ABCA2 1507 497 743
ILF2 - ABCA2 944 1054 2607 ILF2 - ABCA2 831 822 752
ILF3 - ABCA2 1380 1369 1702 ILF3 - ABCA2 1691 2094 2275
ILF3.AS1 - ABCA2 2243 1006 1924 ILF3.AS1 - ABCA2 2058 1664 2165
Ranking of IL family w.r.t ABCE1 Ranking of ABCE1 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1RL2 - ABCE1 906 1403 2365 IL1RL2 - ABCE1 525 2034 723
IL17D - ABCE1 1531 636 753 IL17D - ABCE1 1432 2146 1401
IL17RB - ABCE1 459 2056 1993 IL17RB - ABCE1 1090 2618 263
IL17RD - ABCE1 1030 1332 1565 IL17RD - ABCE1 1523 727 2185
IL33 - ABCE1 1649 719 937 IL33 - ABCE1 2619 808 2025
ILF2 - ABCE1 20 310 560 ILF2 - ABCE1 2650 331 2103
ILF3 - ABCE1 2410 2409 1826 ILF3 - ABCE1 1767 2674 19
ILF3.AS1 - ABCE1 1154 2222 786 ILF3.AS1 - ABCE1 1788 1948 820
Ranking of IL family w.r.t ABCF2 Ranking of ABCF2 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1RL2 - ABCF2 1031 1806 2002 IL1RL2 - ABCF2 2257 818 1274
IL17D - ABCF2 2481 2016 1006 IL17D - ABCF2 796 2104 568
IL17RB - ABCF2 509 1294 2302 IL17RB - ABCF2 1271 621 1631
IL17RD - ABCF2 610 1935 1084 IL17RD - ABCF2 957 2276 1431
IL33 - ABCF2 735 2050 1855 IL33 - ABCF2 421 1781 252
ILF2 - ABCF2 2093 1104 2073 ILF2 - ABCF2 683 2304 529
ILF3 - ABCF2 812 1686 1080 ILF3 - ABCF2 1243 585 1452
ILF3.AS1 - ABCF2 430 2416 1983 ILF3.AS1 - ABCF2 2272 1169 862
Table 20. 2nd order combinatorial hypotheses between IL and ABC family.
Table 20. 2nd order combinatorial hypotheses between IL and ABC family.
Unexplored combinatorial hypotheses
IL w.r.t ABC
IL-1RB/33/F2/F3 ABCA2
IL-1RL2/17D/17RD/33/F2/F3.AS1 ABCE1
IL-17RB/17RD/F3 ABCF2
ABC w.r.t IL
IL-17D/17RD/33/F2 ABCA2
IL-1RL2/17D/17RB/17RD ABCE1
IL-1RL2/17D/17RB/17RD/33/F2/F3/F3.AS1 ABCF2
Table 21. 2nd order combinatorial hypotheses between TNF and IL.
Table 21. 2nd order combinatorial hypotheses between TNF and IL.
Ranking Interleukin family vs TNF family
Ranking of IL family w.r.t TNF Ranking of TNF w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - TNF 1382 727 725 IL1A - TNF 172 660 230
IL1B - TNF 519 539 187 IL1B - TNF 443 458 244
IL1RAP - TNF 1475 1995 2255 IL1RAP - TNF 564 550 1500
IL1RN - TNF 163 106 609 IL1RN - TNF 292 462 276
IL2RG - TNF 276 820 340 IL2RG - TNF 419 708 1035
IL6ST - TNF 2374 2037 2003 IL6ST - TNF 2410 1901 666
IL8 - TNF 921 1325 1148 IL8 - TNF 1072 206 118
IL10RB - TNF 346 595 339 IL10RB - TNF 2065 2120 2296
IL15 - TNF 242 944 616 IL15 - TNF 265 828 279
IL15RA - TNF 2341 1843 2195 IL15RA - TNF 131 914 1488
IL17C - TNF 906 1573 776 IL17C - TNF 2148 568 280
IL17REL - TNF 296 804 677 IL17REL - TNF 1223 1901 11
Ranking of IL family w.r.t TNFAIP1 Ranking of TNFAIP1 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - TNFAIP1 2515 549 1534 IL1A - TNFAIP1 533 1901 1548
IL1B - TNFAIP1 2398 440 2449 IL1B - TNFAIP1 1324 756 1062
IL1RAP - TNFAIP1 326 866 2226 IL1RAP - TNFAIP1 1555 1284 1291
IL1RN - TNFAIP1 1952 649 1453 IL1RN - TNFAIP1 1567 307 979
IL2RG - TNFAIP1 1791 104 2482 IL2RG - TNFAIP1 421 973 1169
IL6ST - TNFAIP1 156 1415 1062 IL6ST - TNFAIP1 1281 104 2086
IL8 - TNFAIP1 456 682 1389 IL8 - TNFAIP1 2293 2126 752
IL10RB - TNFAIP1 97 425 2020 IL10RB - TNFAIP1 716 2092 569
IL15 - TNFAIP1 367 1392 159 IL15 - TNFAIP1 24 436 324
IL15RA - TNFAIP1 1860 1979 611 IL15RA - TNFAIP1 873 2141 1853
IL17C - TNFAIP1 2382 1072 2446 IL17C - TNFAIP1 961 2143 791
IL17REL - TNFAIP1 307 79 161 IL17REL - TNFAIP1 1603 1462 1764
Ranking of IL family w.r.t TNFAIP2 Ranking of TNFAIP2 w.r.t IL family
laplace linear rbf laplace linear rbf
IL1A - TNFAIP2 219 1815 790 IL1A - TNFAIP2 450 1041 465
IL1B - TNFAIP2 210 1123 538 IL1B - TNFAIP2 1923 557 944
IL1RAP - TNFAIP2 1535 660 1525 IL1RAP - TNFAIP2 105 229 845
IL1RN - TNFAIP2 1769 2475 683 IL1RN - TNFAIP2 957 868 839
IL2RG - TNFAIP2 1358 576 188 IL2RG - TNFAIP2 415 1132 613
IL6ST - TNFAIP2 2007 633 1704 IL6ST - TNFAIP2 1649 929 1558
IL8 - TNFAIP2 769 331 368 IL8 - TNFAIP2 1262 1412 1595
IL10RB - TNFAIP2 2319 2497 719 IL10RB - TNFAIP2 93 1583 204
IL15 - TNFAIP2 1362 2383 795 IL15 - TNFAIP2 537 749 120
IL15RA - TNFAIP2 2032 821 1502 IL15RA - TNFAIP2 519 737 1146
IL17C - TNFAIP2 868 1684 1770 IL17C - TNFAIP2 199 424 687
IL17REL - TNFAIP2 279 563 299 IL17REL - TNFAIP2 2057 437 2008
Table 22. 2nd order combinatorial hypotheses between TNF and IL.
Table 22. 2nd order combinatorial hypotheses between TNF and IL.
Ranking Interleukin family vs TNF family
Ranking of IL family w.r.t TNFAIP3 Ranking of TNFAIP3 w.r.t IL 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.t TNFRSF1A Ranking of TNFRSF1A w.r.t IL 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.t TNFRSF10A Ranking of TNFRSF10A w.r.t IL 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 23. 2nd order combinatorial hypotheses between IL and TNF.
Table 23. 2nd order combinatorial hypotheses between IL and TNF.
Ranking Interleukin family vs TNF family
Ranking of IL family w.r.t TNFRSF10B Ranking of TNFRSF10B w.r.t IL 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.t TNFRSF10D Ranking of TNFRSF10D w.r.t IL 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.t TNFRSF12A Ranking of TNFRSF12A w.r.t IL 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.t TNFRSF14 Ranking of TNFRSF14 w.r.t IL 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 24. 2nd order combinatorial hypotheses between IL and TNF.
Table 24. 2nd order combinatorial hypotheses between IL and TNF.
Ranking Interleukin family vs TNF family
Ranking of IL family w.r.t TNFRSF21 Ranking of TNFRSF21 w.r.t IL 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.t TNFRS10 Ranking of TNFRS10 w.r.t IL 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.t TNFRS15 Ranking of TNFRS15 w.r.t IL 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 25. 2nd order combinatorial hypotheses between IL and TNF family.
Table 25. 2nd order combinatorial hypotheses between IL and TNF family.
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
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