Imperial College London

DrMelpomeniKalofonou

Faculty of EngineeringDepartment of Electrical and Electronic Engineering

Research Fellow in Cancer Technology
 
 
 
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Contact

 

+44 (0)20 7594 1594m.kalofonou Website CV

 
 
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Location

 

B420C - Centre for Bio-Inspired Technology (CBIT)Bessemer BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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54 results found

Alexandrou G, Mantikas K-T, Allsopp R, Yapeter CA, Jahin M, Melnick T, Ali S, Coombes RC, Toumazou C, Shaw JA, Kalofonou Met al., 2023, The evolution of affordable technologies in liquid biopsy diagnostics: the key to clinical implementation, Cancers, Vol: 15, ISSN: 2072-6694

Cancer remains a leading cause of death worldwide, despite many advances in diagnosis and treatment. Precision medicine has been a key area of focus, with research providing insights and progress in helping to lower cancer mortality through better patient stratification for therapies and more precise diagnostic techniques. However, unequal access to cancer care is still a global concern, with many patients having limited access to diagnostic tests and treatment regimens. Noninvasive liquid biopsy (LB) technology can determine tumour-specific molecular alterations in peripheral samples. This allows clinicians to infer knowledge at a DNA or cellular level, which can be used to screen individuals with high cancer risk, personalize treatments, monitor treatment response, and detect metastasis early. As scientific understanding of cancer pathology increases, LB technologies that utilize circulating tumour DNA (ctDNA) and circulating tumour cells (CTCs) have evolved over the course of research. These technologies incorporate tumour-specific markers into molecular testing platforms. For clinical translation and maximum patient benefit at a wider scale, the accuracy, accessibility, and affordability of LB tests need to be prioritized and compared with gold standard methodologies in current use. In this review, we highlight the range of technologies in LB diagnostics and discuss the future prospects of LB through the anticipated evolution of current technologies and the integration of emerging and novel ones. This could potentially allow a more cost-effective model of cancer care to be widely adopted.

Journal article

Broomfield J, Kalofonou M, Franklin S, Powell S, Pataillot-Meakin T, Moser N, Bevan C, Georgiou P, Broomfield Jet al., 2023, Handheld ISFET Lab-on-Chip detection of TMPRSS2-ERG and AR mRNA for prostate cancer prognostics, IEEE Sensors Letters, Vol: 7, Pages: 1-4, ISSN: 2475-1472

Ion-sensitive field-effect transistors (ISFETs) in combination with unmodified complementary metal oxide semiconductors present a point-of-care platform for clinical diagnostics and prognostics. This work illustrates the sensitive and specific detection of two circulating mRNA markers for prostate cancer, the androgen receptor and the TMPRSS2-ERG fusion using a target-specific loop-mediated isothermal amplification method. TMPRSS2-ERG and androgen receptor RNA were detected down to 3x10 1 and 5x10 1 copies respectively in under 30 minutes. Administration of these assays onto the ISFET Lab-on-chip device was successful and the specificity of each marker was corroborated with mRNA extracted from prostate cancer cell lines.

Journal article

Broomfield J, Kalofonou M, Franklin S, Powell SM, Pataillot-Meakin T, Moser N, Bevan CL, Georgiou Pet al., 2023, Handheld ISFET Lab-on-Chip detection of TMPRSS2-ERG and AR mRNA for prostate cancer prognostics., IEEE Sens Lett, Vol: 7, Pages: 1-4, ISSN: 2475-1472

Ion-sensitive field-effect transistors (ISFETs) in combination with unmodified complementary metal oxide semiconductors present a point-of-care platform for clinical diagnostics and prognostics. This work illustrates the sensitive and specific detection of two circulating mRNA markers for prostate cancer, the androgen receptor and the TMPRSS2-ERG fusion using a target-specific loop-mediated isothermal amplification method. TMPRSS2-ERG and androgen receptor RNA were detected down to 3x101 and 5x101 copies respectively in under 30 minutes. Administration of these assays onto the ISFET Lab-on-chip device was successful and the specificity of each marker was corroborated with mRNA extracted from prostate cancer cell lines.

Journal article

Tripathi P, Gulli C, Broomfield J, Alexandrou G, Kalofonou M, Bevan C, Moser N, Georgiou Pet al., 2023, Classification of nucleic acid amplification on ISFET arrays using spectrogram-based neural networks., Comput. Biol. Medicine, Vol: 161, Pages: 107027-107027

Journal article

Tripathi P, Gulli C, Broomfield J, Alexandrou G, Kalofonou M, Bevan C, Moser N, Georgiou Pet al., 2023, Classification of nucleic acid amplification on ISFET arrays using spectrogram-based neural networks., Computers in Biology and Medicine, Vol: 161, Pages: 1-11, ISSN: 0010-4825

The COVID-19 pandemic has highlighted a significant research gap in the field of molecular diagnostics. This has brought forth the need for AI-based edge solutions that can provide quick diagnostic results whilst maintaining data privacy, security and high standards of sensitivity and specificity. This paper presents a novel proof-of-concept method to detect nucleic acid amplification using ISFET sensors and deep learning. This enables the detection of DNA and RNA on a low-cost and portable lab-on-chip platform for identifying infectious diseases and cancer biomarkers. We show that by using spectrograms to transform the signal to the time-frequency domain, image processing techniques can be applied to achieve the reliable classification of the detected chemical signals. Transformation to spectrograms is beneficial as it makes the data compatible with 2D convolutional neural networks and helps gain significant performance improvement over neural networks trained on the time domain data. The trained network achieves an accuracy of 84% with a size of 30kB making it suitable for deployment on edge devices. This facilitates a new wave of intelligent lab-on-chip platforms that combine microfluidics, CMOS-based chemical sensing arrays and AI-based edge solutions for more intelligent and rapid molecular diagnostics.

Journal article

Mantikas KT, Moser N, Gulli C, Cunningham D, Georgiou P, Simillis C, Kalofonou Met al., 2023, Detection of the Colorectal Cancer TP53 p.R248W Mutation on a Lab-on-Chip ISFET Platform

This paper describes a method of detection for the TP53 mutation that leads to the p.R248W substitution, commonly found in colorectal cancer cases. This is achieved through the design and implementation of a pH-sensitive and mutation specific Loop-mediated isothermal amplification (pH-LAMP) method and the experimental validation using a Lab-on-Chip (LoC) platform, with an integrated array of Ion-Sensitive Field Effect Transistors (ISFETs) that can detect pH changes. Synthetic TP53 DNA was detected in pH-LAMP reactions, on both a qPCR platform and the LoC, using primers that are specific to each allele (wild-type or mutant). Assays successfully detected the target mutation within 20minutes, demonstrating the potential of the method for multi-target testing. This technology, when coupled with a sample preparation method, could allow for a Point-of-Care genetic testing platform for colorectal cancer to be realised, aiding patient stratification and treatment decisions.

Conference paper

Alexandrou G, Moser N, Ali S, Coombes C, Shaw J, Georgiou P, Toumazou C, Kalofonou Met al., 2023, Distinguishing <i>PIK3CA</i> p.E545K mutational status from pseudogene DNA with a next-generation ISFET sensor array, 56th IEEE International Symposium on Circuits and Systems (ISCAS), Publisher: IEEE, ISSN: 0271-4302

Conference paper

Broomfield J, Kalofonou M, Pataillot-Meakin T, Powell SM, Fernandes RC, Moser N, Bevan CL, Georgiou Pet al., 2022, Detection of YAP1 and AR-V7 mRNA for prostate cancer prognosis using an ISFET lab-on-chip platform, ACS Sensors, Vol: 7, Pages: 3389-3398, ISSN: 2379-3694

Prostate cancer (PCa) is the second most common cause of male cancer-related death worldwide. The gold standard of treatment for advanced PCa is androgen deprivation therapy (ADT). However, eventual failure of ADT is common and leads to lethal metastatic castration-resistant PCa. As such, the detection of relevant biomarkers in the blood for drug resistance in metastatic castration-resistant PCa patients could lead to personalized treatment options. mRNA detection is often limited by the low specificity of qPCR assays which are restricted to specialized laboratories. Here, we present a novel reverse-transcription loop-mediated isothermal amplification assay and have demonstrated its capability for sensitive detection of AR-V7 and YAP1 RNA (3 × 101 RNA copies per reaction). This work presents a foundation for the detection of circulating mRNA in PCa on a non-invasive lab-on-chip device for use at the point-of-care. This technique was implemented onto a lab-on-chip platform integrating an array of chemical sensors (ion-sensitive field-effect transistors) for real-time detection of RNA. Detection of RNA presence was achieved through the translation of chemical signals into electrical readouts. Validation of this technique was conducted with rapid detection (<15 min) of extracted RNA from prostate cancer cell lines 22Rv1s and DU145s.

Journal article

Wormald BW, Moser N, deSouza NM, Mantikas K-T, Malpartida-Cardenas K, Pennisi I, Ind TEJ, Vroobel K, Kalofonou M, Rodriguez-Manzano J, Georgiou Pet al., 2022, Lab-on-Chip assay of tumour markers and Human Papilloma Virus for cervical cancer detection at the point-of-care, Scientific Reports, Vol: 12, ISSN: 2045-2322

Cervical cancer affects over half a million people worldwide each year, the majority of whom are in resource-limited settingswhere cytology screening is not available. As persistent human papilloma virus (HPV) infections are a key causative factor,detection of HPV strains now complements cytology where screening services exist. This work demonstrates the efficacy ofa handheld Lab-on-Chip (LoC) device, with an external sample extraction process, in detecting cervical cancer from biopsysamples. The device is based on Ion-Sensitive Field-Effect Transistor (ISFET) sensors used in combination with loop-mediatedisothermal amplification (LAMP) assays, to amplify HPV DNA and human telomerase reverse transcriptase (hTERT) mRNA.These markers were selected because of their high levels of expression in cervical cancer cells, but low to nil expression innormal cervical tissue. The achieved analytical sensitivity for the molecular targets resolved down to a single copy per reactionfor the mRNA markers, achieving a limit of detection of 102for hTERT. In the tissue samples, HPV-16 DNA was present in 4/5malignant and 2/5 benign tissues, with HPV-18 DNA being present in 1/5 malignant and 1/5 benign tissues. hTERT mRNA wasdetected in all malignant and no benign tissues, with the demonstrated pilot data to indicate the potential for using the LoC incervical cancer screening in resource-limited settings on a large scale.

Journal article

Allsopp R, Alexandrou G, Toumazou C, Ali S, Coombes C, Kalofonou M, Shaw Jet al., 2022, A comparison between Mini-loop mediated isothermal amplification and polymerase spiral reaction for selective amplification of short template DNA, bioRxiv

Journal article

Dimitrakopoulos F-ID, Antonacopoulou AG, Kottorou AE, Kalofonou M, Panagopoulos N, Dougenis D, Makatsoris T, Tzelepi V, Koutras A, Kalofonos HPet al., 2021, Genetic Variations of <i>CD40</i> and <i>LTβR</i> Genes Are Associated With Increased Susceptibility and Clinical Outcome of Non-Small-Cell Carcinoma Patients, FRONTIERS IN ONCOLOGY, Vol: 11, ISSN: 2234-943X

Journal article

Alexandrou G, Moser N, Mantikas K-T, Rodriguez-Manzano J, Ali S, Coombes RC, Shaw J, Georgiou P, Toumazou C, Kalofonou Met al., 2021, Detection of Multiple Breast Cancer ESR1 mutations on an ISFET based Lab-on-Chip Platform., IEEE Trans Biomed Circuits Syst, Vol: PP

ESR1 mutations are important biomarkers in metastatic breast cancer. Specifically, p.E380Q and p.Y537S mu- tations arise in response to hormonal therapies given to patients with hormone receptor positive (HR+) breast cancer (BC). This paper demonstrates the efficacy of an ISFET based CMOS integrated Lab-on-Chip (LoC) system, coupled with variant- specific isothermal amplification chemistries, for detection and discrimination of wild type (WT) from mutant (MT) copies of the ESR1 gene. Hormonal resistant cancers often lead to increased chances of metastatic disease which leads to high mortality rates, especially in low-income regions and areas with low healthcare coverage. Design and optimization of bespoke primers was carried out and tested on a qPCR instrument and then benchmarked versus the LoC platform. Assays for detection of p.Y537S and p.E380Q were developed and tested on the LoC platform, achieving amplification in under 25 minutes and sensitivity of down to 1000 copies of DNA per reaction for both target assays. The LoC system hereby presented, is cheaper and smaller than other standard industry equivalent technologies such as qPCR and sequencing. The LoC platform proposed, has the potential to be used at a breast cancer point-of-care testing setting, offering mutational tracking of circulating tumour DNA in liquid biopsies to assist patient stratification and metastatic monitoring.

Journal article

Jahin M, Fenech-Salerno B, Moser N, Georgiou P, Flanagan J, Toumazou C, De Mateo S, Kalofonou Met al., 2021, Detection of <i>MGMT</i> methylation status using a Lab-on-Chip compatible isothermal amplification method, 43rd Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society (IEEE EMBC), Publisher: IEEE, Pages: 7385-7389, ISSN: 1557-170X

Conference paper

Zhang J, Alexandrou G, Toumazou C, Kalofonou Met al., 2021, Automating the Design of Cancer Specific DNA Probes Using Computational Algorithms, 43rd Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society (IEEE EMBC), Publisher: IEEE, Pages: 1852-1856, ISSN: 1557-170X

Conference paper

Li X, Kalofonou M, 2021, Predicting cancer drug response using an adapted Deep Neural Network model, IEEE International Symposium on Circuits and Systems (IEEE ISCAS), Publisher: IEEE, ISSN: 0271-4302

Conference paper

Dimitrakopoulos F-ID, Kottorou AE, Kalofonou M, Kalofonos HPet al., 2020, The fire within: NF-κB involvement in non–small cell lung cancer, Cancer Research, Vol: 80, Pages: 4025-4036, ISSN: 0008-5472

Thirty-four years since its discovery, NF-κB remains a transcription factor with great potential for cancer therapy. However, NF-κB–targeted therapies have yet to find a way to be clinically translatable. Here, we focus exclusively on the role of NF-κB in non-small cell lung cancer (NSCLC) and discuss its contributing effect on cancer hallmarks such as inflammation, proliferation, survival, apoptosis, angiogenesis, epithelial–mesenchymal transition, metastasis, stemness, metabolism, and therapy resistance. In addition, we present our current knowledge of the clinical significance of NF-κB and its involvement in the treatment of patients with NSCLC with chemotherapy, targeted therapies, and immunotherapy.

Journal article

Alexandrou G, Moser N, Rodriguez-Manzano J, Georgiou P, Shaw J, Coombes C, Toumazou C, Kalofonou Met al., 2020, Detection of breast cancer ESR1 p.E380Q mutation on an ISFET lab-on-chip platform, IEEE International Symposium on Circuits and Systems (ISCAS), Publisher: IEEE, Pages: 1-5, ISSN: 0271-4302

This paper presents a method for detection of ESR1 p.E380Q, a common Breast Cancer (BC) mutation, using an ISFET (Ion-Sensitive Field-Effect Transistor) based Lab-on-Chip (LoC) platform. The LoC contains an ISFET array that can detect pH changes during DNA amplification, specifically Loop-Mediated Isothermal Amplification (LAMP). Synthetic ESR1 DNA was detected in a comparison pH-LAMP assay, carried out on the LoC platform as well as a conventional qPCR instrument. Positive detection of the allele arises due to bespoke allele-specific primers that target one base-pair difference between the wild-type and mutant alleles. The LoC and qPCR demonstrate comparable results detecting the mutant allele with mutant primers in around 25 minutes. The sensing microchip technology coupled with the molecular methods of isothermal chemistries and primer design allow this platform to be tested at a Point-of-Care setting for breast cancer patients, offering mutational tracking platform of circulating tumour DNA in liquid biopsies to assist patient stratification and allow tailored treatments.

Conference paper

Kalofonou M, Malpartida-Cardenas K, Alexandrou G, Rodriguez-Manzano J, Yu L-S, Miscourides N, Allsopp R, LT Gleason K, Goddard K, Fernandez-Garcia D, Page K, Georgiou P, Ali S, Coombes RC, Shaw J, Toumazou Cet al., 2020, A novel hotspot specific isothermal amplification method for detection of thecommon PIK3CA p.H1047R breast cancer mutation, Scientific Reports, Vol: 10, ISSN: 2045-2322

Breast cancer (BC) is a common cancer in women worldwide. Despite advances in treatment, up to 30% of women eventually relapse and die of metastatic breast cancer. Liquid biopsy analysis of circulating cell-free DNA fragments in the patients’ blood can monitor clonality and evolving mutations as a surrogate for tumour biopsy. Next generation sequencing platforms and digital droplet PCR can be used to profile circulating tumour DNA from liquid biopsies; however, they are expensive and time consuming for clinical use. Here, we report a novel strategy with proof-of-concept data that supports the usage of loop-mediated isothermal amplification (LAMP) to detect PIK3CA c.3140 A > G (H1047R), a prevalent BC missense mutation that is attributed to BC tumour growth. Allele-specific primers were designed and optimized to detect the p.H1047R variant following the USS-sbLAMP method. The assay was developed with synthetic DNA templates and validated with DNA from two breast cancer cell-lines and two patient tumour tissue samples through a qPCR instrument and finally piloted on an ISFET enabled microchip. This work sets a foundation for BC mutational profiling on a Lab-on-Chip device, to help the early detection of patient relapse and to monitor efficacy of systemic therapies for personalised cancer patient management.

Journal article

Alexandrou G, Rodriguez-Manzano J, Malpartida-Cardenas K, Georgiou P, Toumazou C, Kalofonou Met al., 2020, In-silico automated allele-specific primer design for loop-mediated isothermal amplification, IEEE International Symposium on Circuits and Systems (ISCAS), Publisher: IEEE, ISSN: 0271-4302

Conference paper

Dimitrakopoulos F-ID, Antonacopoulou AG, Kottorou AE, Panagopoulos N, Kalofonou F, Sampsonas F, Scopa C, Kalofonou M, Koutras A, Makatsoris T, Dougenis D, Papadaki H, Brock M, Kalofonos HPet al., 2019, Expression of intracellular components of the NF-κB alternative pathway (NF-κB2, RelB, NIK and Bcl3) is associated with clinical outcome of NSCLC patients, Scientific Reports, Vol: 9, Pages: 14299-14310, ISSN: 2045-2322

A growing number of studies has shed light on the role of the NF-κΒ in non-small-cell lung cancer (NSCLC). To address the significance of major effectors of the NF-κΒ alternative pathway, we investigated the relationship between NF-κΒ2, RelB, NIK and Bcl3 expression (mRNA and protein) and the clinical outcome of NSCLC patients. NF-κΒ2, RelB, NIK and Bcl3 protein expression levels were assessed by immunohistochemistry in tissue samples from 151 NSCLC patients who had curative resection. mRNA levels were also evaluated in 69 patients using quantitative real-time PCR. Although all studied proteins were overexpressed in NSCLC (P < 0.001 for all), only RelB mRNA levels were strongly increased in cancerous specimens compared to tumor-adjacent non-neoplastic tissues (P = 0.009). Moreover, NF-κB2, RelB and Bcl3 expression was associated with overall survival (OS). In particular, cytoplasmic and mRNA expression of RelB was related to 5-year OS (P = 0.014 and P = 0.006, respectively). Multivariate analysis also showed that Bcl3 expression (nuclear and cytoplasmic) was associated with increased 5-year OS (P = 0.002 and P = 0.036, respectively). In addition, higher Bcl3 mRNA levels were associated with inferior OS in stages I & II and improved OS in stages III and IV after 5-year follow-up (P = 0.004 and P = 0.001, respectively). Furthermore, stage I patients with lower NF-κB2 mRNA levels had better 5-year survival in univariate and multivariate analysis (P = 0.031 and P = 0.028, respectively). Interestingly, RelB expression (cytoplasmic and mRNA) was inversely associated with relapse rates (P = 0.027 and P = 0.015, respectively), while low NIK cytoplasmic expression was associated with lower relapse rates (P = 0.019). Cytoplasmic NIK ex

Journal article

Dimitrakopoulos F-I, Kottorou A, Antonacopoulou A, Panagopoulos N, Scopa C, Kalofonou M, Dougenis D, Koutras A, Makatsoris T, Tzelepi V, Kalofonos Het al., 2019, Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients, Journal of Clinical Medicine, Vol: 8, Pages: 741-741, ISSN: 2077-0383

An increasing number of studies implicates the NF-κB (Nuclear Factor of kappa light chain gene enhancer in B cells) alternative pathway in non-small-cell lung cancer (NSCLC). We assessed the clinical significance of CD40 (Tumor necrosis factor receptor superfamily member 5, TNFRSF5), BAFFR (B-cell activating factor receptor), RANK (Receptor activator of NF-κB) and LTβR (lymphotoxin β receptor) receptors, which activate the alternative pathway of NF-κB, in NSCLC. Evaluation of CD40, BAFFR, RANK and LTβR expression was performed based on the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, while protein expression was assessed by immunohistochemistry in specimens from 119 operated NSCLC patients. CD40 gene overexpression was correlated with improved five-year overall survival (OS) (p < 0.001), while increased BAFFR and LTβR mRNA levels were associated with worse OS in patients with adenocarcinomas (p < 0.001 and p < 0.001, respectively). Similarly, patients with adenocarcinomas exhibited a negative correlation between membranous BAFFR protein expression in carcinoma cells and three- and five-year survival (p = 0.021; HR, 4.977 and p = 0.030; HR, 3.358, respectively) as well as between BAFFR protein overexpression in cancer-associated fibroblasts (CAFs) and two-year survival (p = 0.036; HR, 1.983). Patients with increased LTβR nuclear protein staining or stage II patients with lower cytoplasmic LTβR protein expression had worse five-year OS (p = 0.039 and p = 0.008, respectively). Moreover, CD40 protein expression in tumor infiltrating lymphocytes (TILs) and CAFs was positively associated with metastatic spread while BAFFR protein expression in CAFs was negatively associated with bone metastasis (p = 0.041). Our data suggests that CD40, BAFFR, RANK and LTβR play an important role in NSCLC and further supports the role of NF-κB alternative pathway in NSCLC.

Journal article

Dimtrakopoulos F-ID, Kottorou AE, Antonacopoulou AG, Nikolakopoulos A, Panagopoulos N, Kalofonou M, Dougenis D, Koutras A, Makatsoris T, Tzelepi V, Kalofonos Het al., 2019, Association of BAFFR expression in CAFs with overall survival and response to platinum-based chemotherapy in NSCLC., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X

Conference paper

Dimitrakopoulos F-I, Kottorou A, Antonacopoulou A, Nikolakopoulos A, Panagopoulos N, Kalofonou M, Dougenis D, Koutras A, Makatsoris T, Tzelepi V, Kalofonos Het al., 2019, Association of BAFFR expression in CAFs with overall survival and response to platinum-based chemotherapy in NSCLC, American Society of Clinical Oncology, Publisher: American Society of Clinical Oncology, Pages: 8537-8537, ISSN: 0732-183X

Background: Β-cell activating factor receptor (BAFFR) is a surface receptor, which leads to activation of the Nuclear Factor-kappaB (NF-κB) alternative pathway, a pathway with an important role in non-small cell lung cancer (NSCLC). In addition, cancer associated fibroblasts (CAFs) are major players of the tumor microenvironment promoting NSCLC. The aim of this study was to assess the possible associations of BAFFR expression in CAFs with response to first-line chemotherapy doublet and clinical outcome of NSCLC patients. Methods: Immunohistochemical analysis of BAFFR expression on CAFs was performed on tumor and tumor-adjacent formalin fixed and paraffin embedded tissue samples from 124 operated patients with NSCLC. Patients were under follow-up for at least 60 months, while response to chemotherapy was evaluated in patients who relapsed during this period. Results: BAFFR expression, which was noted exclusively in the cytoplasm of CAFs, was associated with OS only in patients with no infiltration of regional lymph nodes. Higher expression levels of BAFFR in CAFs were related to worse 2-, 3- and 5-year survival (P = 0.015, P = 0.027 and P = 0.040, respectively). This finding persisted after multivariate analysis with age, gender, histological subtype, histological differentiation and disease stage as coefficients (P = 0.009; HR, 2.734; 95% CI, 1.283-5.828). In addition, response to first line chemotherapy was associated with BAFFR expression in CAFs (P = 0.025). Patients who progressed had lower BAFFR levels. Furthermore, BAFFR expression in CAFs was associated with patients’ age. In particular, older patients had higher expression of BAFFR compared to patients younger than 55 years (P = 0.010). Additionally, carcinomas with better differentiation had lower expression of BAFFR in CAFs (P = 0.005). Finally, BAFFR expression in CAFs was related to development of metastatic disease (P = 0.033) and particularly in liver (P = 0,017) and in bones (P = 0.00

Conference paper

Dimitrakopoulos FID, Antonacopoulou A, Kottorou A, Tzelepi V, Panagopoulos M, Kalofonou M, Dougenis D, Koutras A, Makatsoris T, Kalofonos Het al., 2019, 37P Genetic variation of lymphotoxin beta receptor (LTβR) rs10849448 (A/G) is associated with risk for lung cancer and metastatic spread to adrenals, Annals of Oncology, European Lung Cancer Congress 2019, Publisher: Oxford University Press, Pages: mdz073. 016-mdz073. 016

BackgroundDuring the last years there is an expansion of our knowledge in lung cancer immunology. In addition, there is a growing number of studies on the role of lymphotoxin beta receptor (LTβR), a member of the tumor necrosis factor (TNF) family, which plays an important role in lymphoid system formation and homeostasis as well as in immune system regulation mainly through NF-κB signaling. The aim of the current study was to investigate the clinical relevance of LTβR single nucleotide polymorphism (SNP) rs10849448 (A/G) with the susceptibility to NSCLC, the clinicopathological parameters, the relapse and the survival rates of NSCLC patients, as well as with the protein expression of LTβR.MethodsLTβR SNP was genotyped in 268 randomly selected NSCLC patients and 279 age- and gender-matched healthy donors. Immunohistochemical analysis for LTβR was performed on 127 NSCLC tumors. The studied cohort was under observation during a five-year period.ResultsGenotype frequencies of rs10849448 (AA, AG, and GG) varied between healthy controls and patients, but the difference did not reach statistical significance (P = 0.054). AA homozygotes were found to have lower risk for NSCLC compared to G allele carriers in univariate as well as in multivariate analysis (both P = 0.016). Moreover, rs10849448 was associated with development of metastases with A allele carriers developing less often metastatic disease in adrenals (P = 0.013). Interestingly, rs10849448 was related to membranous LTβR protein expression (P = 0.035) in malignant cells, with AA homozygotes being associated with higher protein levels.ConclusionsThe present findings suggest that the investigated SNP rs10849448 may be associated with NSCLC initiation as well as with the development of metastatic disease. More association and functional studies are needed in order to further clarify it’s role in NSCLC.

Conference paper

Dimitrakopoulos F-ID, Antonacopoulou A, Kottorou A, Tzelepi V, Panagopoulos N, Kalofonou M, Dougenis D, Koutras A, Makatsoris T, Kalofonos Het al., 2019, Genetic variation of lymphotoxin beta receptor (LTβR) rs10849448 (A/G) is associated with risk for lung cancer and metastatic spread to adrenals., Ann Oncol, Vol: 30 Suppl 2

Journal article

Zhao Z, Li K, Toumazou C, Kalofonou Met al., 2019, A computational model for anti-cancer drug sensitivity prediction, IEEE Biomedical Circuits and Systems Conference (BioCAS), Publisher: IEEE, ISSN: 2163-4025

Conference paper

Khwaja M, Kalofonou M, Toumazou C, 2018, A Deep Autoencoder System for Differentiation of Cancer Types Based on DNA Methylation State, arXiv preprint arXiv:1810.01243

Journal article

Ma D, Rodriguez-Manzano J, Lopez SDM, Kalofonou M, Georgiou P, Toumazou Cet al., 2018, Adapting ISFETs for Epigenetics: An Overview, IEEE Transactions on Biomedical Circuits and Systems, Vol: 12, Pages: 1186-1201, ISSN: 1932-4545

This paper gives an overview of how CMOS design methods can be applied to ion-sensitive field effect transistor (ISFETs) for pH-based DNA methylation and miRNA detection. Design specifications are fundamentally defined by the choice of analysis. As such, the focus for DNA methylation was on developing front-end analogue circuits to carry out Methylation-specific PCR (MSP) for Point-of-Care applications, and sequencing for detailed analysis. The use of MSP prompted the design of an ISFET weak inversion current mirror topology for differential sensing and reduction of drift and temperature sensitivities. The primary limitation in ion-semiconductor sequencing is base calling of repeated nucleotides known as homopolymers. Implementation of a switched current integrator can potentially increase both accuracy and window for detection, within the frequency region of DNA reactions. For quantifying miRNAs, digital back-end processing circuits were considered toward a fully portable platform that can carry out real-time monitoring of DNA amplification reactions. Two systems to evaluate threshold cycles were developed, based on the Derivative method and a new proposed 3-point exponential evaluation aim to reduce detection time simultaneously. Both implementations were tested with datasets from fluorescent qPCR reactions, as well as pH-LAMP experiments that have been optimized for on-chip amplifications. All designs were fabricated in unmodified CMOS with performance assessed based on functionality as well as pH-resolution required in practice.

Journal article

Hall DA, Kalofonou M, 2018, Guest Editorial ISCAS 2017 Special Issue, IEEE Transactions on Biomedical Circuits and Systems, Vol: 12, Pages: 449-451, ISSN: 1932-4545

Journal article

Gantier M, Kalofonou M, Toumazou C, 2018, A trapped charge compensation scheme for ISFET based translinear circuits, IEEE International Symposium on Circuits and Systems (ISCAS), Publisher: IEEE

A trapped charge compensation scheme for ISFET based translinear circuits is presented, as part of a system for prediction of cancer risk, based on DNA methylation. Each pixel is able to measure a DNA methylation ratio through pH-based measurements and by using in-pixel comparison to a tunable threshold, to output a result which indicates percentage of methylation used as a cancer score. The developed system was designed in a 0.35 μm CMOS technology and uses a novel trapped charge compensation scheme for ISFETs used in translinear circuits. The output scheme was able to compensate trapped charge of up to 380mV, with a ratio error below 5%, in a range of ratios between 50% and 80% which is generated from pH-based DNA methylation reactions.

Conference paper

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