• Lymphatic vessel density, microvessel density and lymphangiogenic growth factor expression in colorectal cancer.

      Duff, Sarah E; Jeziorska, M; Kumar, Shant; Haboubi, Najib; Sherlock, David J; O'Dwyer, Sarah T; Jayson, Gordon C; Department of Surgery, Christie Hospital NHS Trust, Manchester, UK. saraheduff@aol.com (2007-11)
      OBJECTIVE: Microvessel density (MVD) has been studied as a prognostic marker in human cancers. Quantification of lymphatic vessel density (LVD) is now possible by using new antibodies. Expression of the lymphangiogenic growth factors, VEGF-C and VEGF-D, is associated with poorer clinicopathological outcomes in various tumours. The aim of this study was to quantify LVD and MVD in colorectal cancer, determine the relationship between LVD, MVD and clinicopathological variables and examine the relationship between LVD and tumour expression of VEGF-C and VEGF-D. METHOD: Thirty primary colorectal cancers were immunostained for CD34, lymph vessel endothelial hyaluronan receptor-1 (LYVE-1), VEGF-A and VEGF-D using standard techniques. LVD and MVD were determined by Chalkley grid counting. Tumours were assessed for the presence or absence of LYVE-1 positive lymphatics at different areas within the tumour and the tumour was scored for VEGF-C and VEGF-D immunostaining intensity at the invading tumour edge. Non-parametric tests were used for statistical analysis and a P-value of <0.05 was taken as significant. RESULTS: Lymph vessel endothelial hyaluronan receptor-1 was an excellent lymphatic vessel marker. Within normal bowel wall, lymphatic vessels were found rarely in the superficial colonic mucosa, but were numerous in the submucosa and muscularis propria. In the majority of tumours, lymphatic vessels were located in the peri-tumoural area, intra-tumoural vessels were sparse and tended to be narrow with closed lumina. At the invading tumour edge, VEGF-C expression was higher (P = 0.028) and VEGF-D expression lower (P = 0.011), in tumours in which lymphatic vessels were present. No significant differences between LVD and any clinicopathological variable or route of metastasis were identified. CONCLUSION: Lymphatic vessel density and MVD can be quantified in colorectal carcinoma using immunohistochemical techniques. The balance between expression of VEGF-C and VEGF-D at the invading tumour edge may enhance lymphatic metastasis, by promoting tumour lymphangiogenesis or by activation of pre-existing lymphatic vessels. No relationship was identified between LVD and clinicopathological variables.
    • Lymphocyte migration across high endothelium is associated with increases in alpha 4 beta 1 integrin (VLA-4) affinity.

      Hourihan, H; Allen, Terence D; Ager, A; Department of Cell and Structural Biology, University of Manchester, UK. (1993-04)
      The constitutive recirculation of lymphocytes between the widely distributed organs of the immune system is essential for host defence. We have developed an in vitro model of lymphocyte migration from the blood into lymph nodes which employs primary cultures of high endothelial cells (HEC). HEC-adherent lymphocytes adopt one of two distinct morphologies which correlates with their position in the endothelial layer; type I cells are bound to the surface of HEC and type II cells are underneath the endothelial layer. In a previous study we reported that the numbers of type I and type II cells are independently regulated, however the relationship between these two lymphocyte populations was not determined. In this study we have carried out detailed kinetic, phenotypic and functional analyses of type I and type II lymphocytes and determined their relationship. Using allotype marked lymphocytes from the PVG.RT7a and PVG.RT7b rat strains in a pulse-chase analysis, type I and type II lymphocytes were found to represent the same population of lymphocytes at different stages of interaction with the endothelial layer, rather than representing two independent lymphocyte populations. Migration was an irreversible event and the efficiency of migration (i.e. transition from type I to type II) was related to the concentration of lymphocytes plated on to the HEC layer. Following transmigration lymphocytes showed an increased ability to migrate across HEC layers and to bind to immobilised CS1 peptide. The increased binding to CS1 peptide was transient and fell to control levels over a 3 hour time period. The expression of alpha 4 integrin subunit on lymphocytes was unchanged following migration which suggests that the affinity of the CS1 receptor, alpha 4 beta 1, is upregulated by interaction with HEC. Together these results suggest that transendothelial migration is regulated by increases in the affinity of alpha 4 beta 1 integrin on lymphocytes following contact with HEC.
    • Lymphocyte migration into three-dimensional collagen matrices: a quantitative study.

      Schor, Seth L; Allen, Terence D; Winn, B; CRC Department of Medical Oncology, Christie Hospital and Holt Radium Institute, Manchester M20 9BX (1983-04)
      Lymphocytes have been plated onto the surface of three-dimensional gels of native collagen fibers, and their distribution throughout the three-dimensional collagen matrix has been determined in a quantitative fashion at various times thereafter. Information regarding the total number of applied cells may be obtained by this means. Lymphocyte penetration into the collagen gel does not appear to involve the expression of collagenolytic activity, nor does it require the presence of serum. Analysis of the kinetics of lymphocyte penetration into the gel matrix indicates that lymphocytes are migrating in a "random-walk" fashion. Our objective has been to establish a model system for studying the cell-matrix and cell-cell interactions which influence the pattern of lymphocyte recirculation in vivo and the results presented here are discussed in this context.
    • Lymphocyte radiosensitivity is a significant prognostic factor for morbidity in carcinoma of the cervix.

      West, Catharine M L; Davidson, Susan E; Elyan, S A; Valentine, Helen R; Roberts, Stephen A; Swindell, Ric; Hunter, Robin D; CRC Experimental Radiation Oncology Group, Paterson Institute for Cancer Research, Manchester, United Kingdom. cwest@picr.man.ac.uk (2001-09-01)
      PURPOSE: To study the relationship between pretreatment peripheral blood lymphocyte radiosensitivity and morbidity following radiation therapy. METHODS AND MATERIALS: A prospective study was carried out in which patients with carcinoma of the cervix underwent radiation therapy. Intrinsic radiosensitivity was measured on pretreatment peripheral blood lymphocytes, using a limiting dilution clonogenic assay. Late morbidity was assessed using the Franco-Italian glossary. Results were correlated in an actuarial analysis. RESULTS: There were no correlations between the measured lymphocyte radiosensitivity (SF2) and colony-forming efficiency, patient age, tumor grade, or disease stage. For 83 patients, lymphocyte SF2 was a significant prognostic factor for the probability of developing both any (p = 0.002) and Grade 3 (p = 0.026) morbidity. In 174 patients, stage showed borderline significance as a prognostic factor for morbidity (p = 0.056). However, the type of treatment (intracavitary alone, intracavitary plus parametrial irradiation, single insertion plus whole-pelvis irradiation) was significantly associated with the probability of developing late complications (p = 0.013). There was a weak significant inverse correlation between lymphocyte SF2 and grade of morbidity (r = -0.34, p = 0.002). CONCLUSION: These data highlight the importance of normal cell radiosensitivity as a factor determining radiation therapy response. They also show that peripheral blood lymphocyte SF2 is a highly significant prognostic factor for the probability of developing late radiation morbidity, and that carcinoma of the cervix is a good model for testing radiobiologic principles in the clinic.
    • Lymphocyte telomere length correlates with in vitro radiosensitivity in breast cancer cases but is not predictive of acute normal tissue reactions to radiotherapy.

      Iwasaki, Toshiyasu; Robertson, Naomi; Tsigani, Theodora; Finnon, Paul; Scott, David A; Levine, Edward; Badie, Christophe; Bouffler, Simon; Radiation Effects Department, Health Protection Agency, Centre for Radiation, Chemical and Environmental Hazards, Radiation Protection Division, Chilton, Didcot, Oxfordshire, UK. (2008-04)
      PURPOSE: To examine the hypothesis that lymphocyte telomere length may be predictive of both breast cancer susceptibility and severity of acute reactions to radiotherapy. MATERIALS AND METHODS: Peripheral blood lymphocyte cultures from breast cancer patients (with normal or severe skin reactions to radiotherapy) and normal individuals were assessed for in vitro radiosensitivity as measured by apoptosis, cell cycle delay and cytotoxicity. Telomere lengths were determined by a flow cytometric fluorescence in situ hybridization assay (FLOW-FISH). RESULTS: Female breast cancer cases (n = 24) had reduced lymphocyte telomere lengths by comparison with healthy controls (n = 20, p < 0.04). However, the average age of healthy controls was less (45.4) than cases (53). When the control group was modified to give a better age match (51.5, n = 13) the reduced telomere length in cases was not significantly different from controls. Lymphocytes from breast cancer cases also showed reduced cell cycle delay (p < 0.001) and increased apoptosis (p < 0.01) following irradiation in vitro at 3 and 5 Gy respectively, compared to healthy controls. Statistical significance was maintained with the improved age matching of groups. Comparison of lymphocytes from breast cancer patients with normal (n = 11) and severe (n = 13) skin reactions to radiotherapy failed to identify differences in telomere length or cellular radiosensitivity in this limited sample. CONCLUSIONS: This study adds to the evidence suggesting a correlation between altered cellular radiosensitivity and breast cancer. However, in the cases investigated, telomere length does not appear to be predictive of acute skin reactions to radiotherapy.
    • Lymphoid-specific expression of the Id3 gene in hematopoietic cells. Selective antagonism of E2A basic helix-loop-helix protein associated with Id3-induced differentiation of erythroleukemia cells.

      Deed, Richard W; Jasiok, Michelle; Norton, John D; CRC Department of Gene Regulation, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 9BX, United Kingdom. (1998-04-03)
      Accumulating evidence implicates functions of the Id family of helix-loop-helix proteins in the regulation of cell growth and differentiation in metazoa. Within the mammalian hematopoietic organ, expression of the Id3 gene is restricted to the lymphoid cell compartment. We show here that in non-lymphoid hematopoietic cells, repression of transcription is correlated with hypermethylation of sequences in the vicinity of the upstream regulatory region of the Id3 gene, suggestive of a strict developmental control of expression of this gene in lymphoid versus non-lymphoid hematopoietic cells. Enforced ectopic expression of Id3 in K562 erythroid progenitor cells promotes erythroid differentiation and is correlated with a quantitative/qualitative shift in the profile of interacting TAL1 and E protein heterodimers that bind to a consensus E box sequence in in vitro band shift assays, consistent with selective targeting of E2A E protein(s) by Id3 and suggesting a possible mechanism involving TAL1-mediated differentiation. By using a Gal 4-VP16 two-hybrid competition assay and an E box-dependent reporter assay, we demonstrate directly that the E2A protein E47 preferentially associates with Id3 in vivo. These observations provide a paradigm for understanding how overlapping but distinct specificities of individual Id proteins may constitute a developmentally regulated program underlying cell determination in diverse lineages.
    • Lymphokine activated killing of fresh human leukaemias.

      Dawson, M; Johnston, D; Taylor, G; Moore, Michael; Department of Immunology, Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester M20 9BX. (1986)
      The relative susceptibility of 10 human leukaemias comprising acute phase leucocytes from 5 acute myeloid and 5 lymphoid neoplasms, and 2 immunoblastic lymphomas to killing by peripheral blood mononuclear cells (PBMC), before and after target cell treatment with phytohaemagglutinin (PHA), and by interleukin-2 (IL-2) activated peripheral blood lymphocytes (PBL) was investigated in short term 51Cr release assays using effector cells from 10 allogeneic donors. Optimal lectin-dependent cellular cytotoxicity (LDCC) was verified against K562 and L1210 cells and lymphokine-activated killing (LAK) against K562 and Daudi cells. Under these conditions, the majority of the leukaemias tested revealed only a finite sensitivity to any of the cytotoxic mechanisms, which was dependent on the donor origin of the effectors. The leukaemias were more consistently susceptible to LDCC than LAK and removal of adherent cells to enrich for the latter activity in effector populations, was ineffective. Lymphocytes from a patient in long term (greater than 5 yr) remission exhibited LAK against the autologous target E84, a natural killer (NK)-sensitive acute myelomonocytic leukaemia. These cells failed to cross-compete for lysis of K562 by LAK cells, suggesting the existence of different recognition structure(s) on the two targets.
    • Lymphoma and leukaemia due to drugs.

      Geary, C; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester M20 9BX (1980-12)
    • Lysine and arginine side chains in glycosaminoglycan-protein complexes investigated by NMR, cross-linking, and mass spectrometry: a case study of the factor H-heparin interaction.

      Blaum, Bärbel S; Deakin, Jon A; Johansson, Conny M; Herbert, Andrew P; Barlow, Paul N; Lyon, Malcolm; Uhrín, Dusan; Edinburgh Biomolecular NMR Unit, School of Chemistry and School of Biological Sciences, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, Scotland, United Kingdom. (2010-05-12)
      We have used the interaction between module 7 of complement factor H (CFH approximately 7) and a fully sulfated heparin tetrasaccharide to exemplify a new approach for studying contributions of basic side chains to the formation of glycosaminoglycan (GAG)-protein complexes. We first employed HISQC and H(2)CN NMR experiments to monitor the side-chain resonances of lysines and arginines in (15)N, (13)C-labeled protein during titrations with a fully sulfated heparin tetrasaccharide under physiological conditions. Under identical conditions and using (15)N-labeled protein, we then cross-linked tetrasaccharide to CFH approximately 7 and confirmed the 1:1 stoichiometry by FT-ICR-MS. We subsequently characterized this covalent protein-GAG conjugate by NMR and further MS techniques. MALDI-TOF MS identified protein fragments obtained via trypsin digestion or chemical fragmentation, yielding information concerning the site of GAG attachment. Combining MS and NMR data allowed us to identify the side chain of K405 as the point of attachment of the cross-linked heparin oligosaccharide to CFH approximately 7. On the basis of the analysis of NMR and MS data of the noncovalent and cross-linked CFH approximately 7-tetrasaccharide complexes, we conclude that the K446 side chain is not essential for binding the tetrasaccharide, despite the large chemical shift perturbations of its backbone amide (15)N and (1)H resonances during titrations. We show that R444 provides the most important charge-charge interaction within a C-terminal heparin-binding subsite of CFH approximately 7 whereas side chains of R404, K405, and K388 are the predominant contributors to an N-terminal binding subsite located in the immediate vicinity of residue 402, which is implicated in age-related macular degeneration (AMD).
    • Lysis of alloantibody-sensitized human erythrocytes by peripheral blood mononuclear cells: heterogeneity of effector populations.

      Kimber, Ian; Moore, Michael (1981-01)
      Cell-mediated haemolysis of human erythrocytes (HRBC) mediated by sensitizing alloantibodies of two specificities was studied using the 51Cr release assay. Peripheral blood mononuclear cells (PBMC) were found capable fo lysing HRBC of phenotype ARh(D) + ve sensitized with either anti-D or "natural" anti-A antibodies. The characteristics of the effector population, however, were dependent upon the sensitizing antibody. HRBC sensitized with anti-A were lysed by a radioresistant, silica- and carrageenan-sensitive population which could be selectively removed by adherence. Sensitization with rhesus antibody induced cytotoxicity by a population which was radiosensitive and relatively unaffected by removal of adherent cells or by treatment with silica or carrageenan. The results demonstrate that the antigen-antibody interaction, rather than the target cell type, determines which effector cells participate in antibody-dependent cellular cytotoxicity (ADCC) against human red cells.
    • Lysis of fresh human tumor cells by autologous large granular lymphocytes and T-lymphocytes: two distinct killing activities induced by coculture with autologous tumor.

      Uchida, Atsushi; Moore, Michael; Paterson Institute for Cancer Research, Manchester, United Kingdom. (1984-12)
      The specific and natural killer (NK)-restricted nature of autologous tumor killing by blood lymphocytes was studied in patients with carcinomatous pleural effusions. Large granular lymphocytes (LGL) and small T-lymphocytes were isolated by centrifugation on discontinuous Percoll density gradients. Tumor cells freshly isolated from pleural effusions of cancer patients were classified according to their susceptibility to purified LGL from normal donors in a 4-hour 51Cr release assay. Of 15 NK-sensitive tumors, 14 were lysed by fresh autologous LGL, whereas only 2 were killed by T-cells. Neither LGL nor T-cells were cytotoxic to NK-resistant autologous tumor. LGL and T-cells were then cultured in vitro with autologous tumor cells for 6 days. In 13 of 15 autologous mixed lymphocyte-tumor cultures (MLTC) NK-sensitive tumor-cultured LGL maintained their autotumor killing activity, whereas LGL cultured alone lost the activity. Depletion of high-affinity sheep erythrocyte-rosetting cells from Percoll-purified LGL resulted in an enrichment of effector cells. LGL from autologous MLTC were able to kill NK-susceptible allogeneic effusion tumor and K562 as were fresh LGL. No lysis of NK-resistant autologous tumor was observed with cultured LGL. In contrast, activation of T-cells in autologous MLTC resulted in the generation of autotumor killer cells in 10 of 15 NK-sensitive and 3 of 6 NK-resistant tumor samples. However, cultured T-cells were incapable of killing allogeneic tumor and K562. In autologous MLTC T-cells proliferated in response to autologous tumor, whereas no proliferation was observed in the culture of LGL. The enrichment of blasts from cultured T-cells on discontinuous Percoll gradients induced an augmentation of autotumor cytotoxicity, with no reactivity in blast-depleted, small, resting T-lymphocytes. These results indicated that 2 distinct types of autotumor-recognizing lymphocytes, LGL and T-cells, are present in the peripheral blood of cancer patients.
    • Lysis of fresh human tumour cells by autologous tumour-associated lymphocytes: Two distinct types of autologous tumour killer cells induced by co-culture with autologous tumour

      Uchida, Atsushi; Moore, Michael; Division of Immunology, Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester M20 9BX, England. (1985)
    • Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.

      Tang, Haoran; Leung, L; Saturno, Grazia; Viros, Amaya; Smith, Duncan L; Di Leva, Gianpiero; Morrison, Eamonn; Niculescu-Duvaz, D; Lopes, F; Johnson, L; et al. (2017-04-18)
      Lysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking the extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that LOX regulates the epidermal growth factor receptor (EGFR) to drive tumour progression. We show that LOX regulates EGFR by suppressing TGFβ1 signalling through the secreted protease HTRA1. This increases the expression of Matrilin2 (MATN2), an EGF-like domain-containing protein that traps EGFR at the cell surface to facilitate its activation by EGF. We describe a pharmacological inhibitor of LOX, CCT365623, which disrupts EGFR cell surface retention and delays the growth of primary and metastatic tumour cells in vivo. Thus, we show that LOX regulates EGFR cell surface retention to drive tumour progression, and we validate the therapeutic potential of inhibiting this pathway with the small molecule inhibitor CCT365623.
    • Lysyl oxidase regulates cell surface EGFR, and directionality of cancer cell invasion

      Tang, Haoran; Springer, Caroline; Marais, Richard; CRUK Manchester Insitute, Manchester (2018)
    • Lysyl oxidase regulates cell surface EGFR, and directionality of cancer cell invasion.

      Tang, Haoran; Springer, Caroline; Marais, Richard; Canc Res UK Manchester Inst, Manchester, Lancs, England (2018)
    • Lysyl oxidase: from basic science to future cancer treatment.

      Nishioka, T; Eustace, A J; West, Catharine M L; Department of Biomedical Sciences and Engineering, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan. (2012)
      In this mini-review, we discuss the physiological and pathological roles of lysyl oxidase (LOX) and its family, LOX-like proteins (LOXL), in relation to prognosis of major cancers. The number of reports on LOX family is numerous. We have decided to review the articles that were recently published (i.e. past 5 years). Experimental techniques in molecular biology have advanced surprisingly in the past decade. Accordingly, the results of the studies are more reliable. Most studies reached the same conclusion; a higher LOX- or LOXL- expression is associated with a poor prognosis. Molecular experiments have already started aiming for clinical application, and the results are encouraging. Suppressing LOX or LOXL activities resulted in lower cell motility in collagen gel and, moreover, succeeded in reducing metastases in mice. LOX family members were originally recognized as molecules that cross-link collagen fibers in the extracellular matrix. Recent studies demonstrated that they are also involved in a phenomenon called Epithelial Mesenchymal Transition (EMT). This may affect cell movement and cancer cell invasiveness. LOX and LOXL2 are regulated by hypoxia, a major factor in the failure of cancer treatment. Here we discuss the molecular biology of the LOX family in relation to its role in tumor biology.
    • The M-CSF receptor substrate and interacting protein FMIP is governed in its subcellular localization by protein kinase C-mediated phosphorylation, and thereby potentiates M-CSF-mediated differentiation.

      Mancini, Annalisa; Koch, Alexandra; Whetton, Anthony D; Tamura, Teruko; Institut für Biochemie, OE 4310, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, D-30623 Hannover, Germany. (2004-08-26)
      Macrophage colony-stimulating factor (M-CSF or CSF-1) and its cognate receptor, the tyrosine kinase c-fms, are essential for monocyte and macrophage development. We have recently identified an Fms-interacting protein (FMIP) that binds transiently to the cytoplasmic domain of activated Fms molecules and is phosphorylated on tyrosine by Fms tyrosine kinase. FMIP is a substrate not only for Fms but also for protein kinase C (PKC). Mutagenesis reveals that this occurs on serines 5 and 6. Adjacent to these sites is a nuclear localization signal (NLS). We show that this NLS is essential for the predominantly nuclear localization of FMIP. Generation of phosphomimetic substitutions on serine residues 5 and 6 confirms that PKC-mediated phosphorylation on this site leads to translocation of FMIP to the cytosol. Furthermore, the mutant FMIP (FMIPSS5,6AA) was detected abundantly in the nucleus even in the presence of activated PKCalpha. Wild-type FMIP and FMIPSS5,6AA inhibited M-CSF-mediated survival signaling, while FMIPSS5,6EE-expressing cells survived and differentiated into macrophages more efficiently than wild-type cells in the presence of M-CSF or TPA. We conclude M-CSF-mediated activation of PKCalpha can potentiate FMIP action to initiate survival/differentiation signaling.
    • Machine learning and data mining frameworks for predicting drug response in cancer: an overview and a novel in silico screening process based on association rule mining

      Vougas, K; Sakellaropoulos, T; Kotsinas, A; Foukas, GP; Ntargaras, A; Koinis, F; Polyzos, A; Myrianthopoulos, V; Zhou, H; Narang, S; et al. (2019)
      A major challenge in cancer treatment is predicting the clinical response to anti-cancer drugs on a personalized basis. The success of such a task largely depends on the ability to develop computational resources that integrate big "omic" data into effective drug-response models. Machine learning is both an expanding and an evolving computational field that holds promise to cover such needs. Here we provide a focused overview of: 1) the various supervised and unsupervised algorithms used specifically in drug response prediction applications, 2) the strategies employed to develop these algorithms into applicable models, 3) data resources that are fed into these frameworks and 4) pitfalls and challenges to maximize model performance. In this context we also describe a novel in silico screening process, based on Association Rule Mining, for identifying genes as candidate drivers of drug response and compare it with relevant data mining frameworks, for which we generated a web application freely available at: https://compbio.nyumc.org/drugs/. This pipeline explores with high efficiency large sample-spaces, while is able to detect low frequency events and evaluate statistical significance even in the multidimensional space, presenting the results in the form of easily interpretable rules. We conclude with future prospects and challenges of applying machine learning based drug response prediction in precision medicine.
    • Machine learning approaches on high throughput NGS data to unveil mechanisms of function in biology and disease

      Pezoulas, V. C.; Hazapis, O.; Lagopati, N.; Exarchos, T. P.; Goules, A. V.; Tzioufas, A. G.; Fotiadis, D. I.; Stratis, I. G.; Yannacopoulos, A. N.; Gorgoulis, Vassilis G; et al. (2021)
      In this review, the fundamental basis of machine learning (ML) and data mining (DM) are summarized together with the techniques for distilling knowledge from state-of-the-art omics experiments. This includes an introduction to the basic mathematical principles of unsupervised/supervised learning methods, dimensionality reduction techniques, deep neural networks architectures and the applications of these in bioinformatics. Several case studies under evaluation mainly involve next generation sequencing (NGS) experiments, like deciphering gene expression from total and single cell (scRNA-seq) analysis; for the latter, a description of all recent artificial intelligence (AI) methods for the investigation of cell sub-types, biomarkers and imputation techniques are described. Other areas of interest where various ML schemes have been investigated are for providing information regarding transcription factors (TF) binding sites, chromatin organization patterns and RNA binding proteins (RBPs), while analyses on RNA sequence and structure as well as 3D dimensional protein structure predictions with the use of ML are described. Furthermore, we summarize the recent methods of using ML in clinical oncology, when taking into consideration the current omics data with pharmacogenomics to determine personalized treatments. With this review we wish to provide the scientific community with a thorough investigation of main novel ML applications which take into consideration the latest achievements in genomics, thus, unraveling the fundamental mechanisms of biology towards the understanding and cure of diseases.