Search results for: gynecological cancer

Authors: Maryam Hajrezaie, Mahmood Ameen Abdulla, Nazia AbdulMajid, Maryam Zahedifard

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Colon cancer is one of the most prevalent cancers in the world. Cancer chemoprevention is defined as the use of natural or synthetic compounds capable of inducing biological mechanisms necessary to preserve genomic fidelity. New schiff based compounds are reported to exhibit a wide spectrum of biological activities of therapeutic importance. To evaluate inhibitory properties of CdCl2(C14H21N3O2) complex on colonic aberrant crypt foci, five groups of 7-week-old male rats were used. Control group was fed with 10% Tween 20 once a day, cancer control group was intra-peritoneally injected with 15 mg/kg Azoxymethan, drug control group was injected with 15 mg/kg azoxymethan and 5-Flourouracil, experimental groups were fed with 2.5 and 5 mg/kg CdCl2(C14H21N3O2) compound each once a day. Administration of compound were found to be effectively chemoprotective. Andrographolide suppressed total colonic ACF formation up to 72% to 74%, respectively, when compared with control group. The results also showed a significant increase in glutathione peroxidase, superoxide dismutase, catalase activities and a decrease in malondialdehyde level. Immunohistochemical staining demonstrated down-regulation of PCNA protein. According to the Western blot comparison analysis, COX-2 and Bcl2 is up-regulated whilst the Bax is down-regulated. according to these data, this compound plays promising chemoprotective activity, in a model of AOM-induced in ACF.

Keywords: chemopreventive, Schiff based compound, aberrant crypt foci (ACF), immunohistochemical staining

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Authors: Lucian Mocan, Flaviu Tabaran, Teodora Mocan, Cristian Matea, Cornel Iancu

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We present method of Gold Nanoparticle enhanced laser thermal ablation of HepG2 cells (Human hepatocellular liver carcinoma cell line), based on a simple gold nanoparticle carrier system, such as serum albumin (BSA), and demonstrate its selective therapeutic efficacy. Hyperspectral, contrast phase, and confocal microscopy combined immunochemical staining were used to demonstrate the selective internalization of HSA-GNPs via Gp60 receptors and the caveolin-mediated endocytosis inside HepG2 cells. We examined the ability of laser-activated carbon nanotubes to induce Hsp70 expression using confocal microscopy. Hep G2 cells heat-shocked (laser activated BSA-GNPs) to 42°C demonstrated an up-regulation of Hsp70 compared with control cells (BSA-GNPs treated cells without laser), which showed no detectable constitutive expression of Hsp70. We observed a time-dependent induction in Hsp70 expression in Hep G2 treated with BSA-GNPs and LASER irradiated. The post-irradiation apoptotic rate of HepG2 cells treated with HSA-GNPs ranged from 88.24% (for 50 mg/L) at 60 seconds, while at 30 minute the rate increased to 92.34% (50 mg/L). These unique results may represent a major step in liver cancer treatment using nanolocalized thermal ablation by laser heating.

Keywords: gold nanoparticles, liver cancer, albumin, laser irradiation

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Authors: Felicia Segeth, Florian G. Klein, Lea Berger, Andreas Kolk, Per S. Holm

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The entry of oncolytic viruses (OVs) into clinical application opens groundbreaking changes in current and future treatment regimens. However, despite their potent anti-cancer activity in vitro, clinical studies revealed limitations of OVs as monotherapy. The same applies to CDK 4/6 inhibitors (CDK4/6i) targeting cell cycle as well as bromodomain and extra-terminal domain inhibitors (BETi) targeting gene expression. In this study, the anti-tumoral effect of XVir-N-31, an YB-1 dependent oncolytic adenovirus, was evaluated in combination with Ribociclib, a CDK4/6i, and JQ1, a BETi. The head and neck squamous cell carcinoma (HNSCC) cell lines Fadu, SAS, and Cal-33 were used. DNA replication and gene expression of XVir-N-31 was measured by RT-qPCR, protein expression by western blotting, and cell lysis by SRB assays. Treatment with CDK4/6i and BETi increased viral gene expression, viral DNA replication, and viral particle formation. The data show that the combination of oncolytic adenovirus XVir-N-31 with CDK4/6i & BETi acts highly synergistic in cancer cell lysis. Furthermore, additional molecular analyses on this subject demonstrate that the positive transcription elongation factor P-TEFb plays a decisive role in this regard, indicating an influence of the combinational therapy on gene transcription control. The combination of CDK4/6i & BETi and XVir-N-31 is an attractive strategy to achieve substantial cancer cell killing and is highly suitable for clinical testing.

Keywords: adenovirus, BET, CDK4/6, HNSCC, P-TEFb, YB-1

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Authors: Tomohiro Uchida, Noriaki Satake, Toshimichi Nakaho, Akira Inoue, Hidemitsu Saito

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In this study, we assessed the bereavement risk of family caregivers of patients with cancer. In the palliative care unit of Tohoku University Hospital, we conducted a family psychoeducation session to support the family caregivers of patients with cancer. A total of 50 participants (8 males and 42 females; mean age = 62.98 years, SD = 11.10) were assessed after the session for bereavement risk using the Japanese version of the Bereavement Risk Assessment Tool (BRAT-J). According to the BRAT-J scores, eight participants were considered to be having no known risk (Level 1), seventeen had minimal risk (Level 2), twenty had a low risk (Level 3), four had a moderate risk (Level 4), and one had a high risk (Level 5). Of these participants, seven participants had completed the follow-up postal survey that assessed their psychological distress (the Kessler Psychological Distress Scale: K6) to compare the bereavement risk. According to the K6 scores, three-fourth of the individuals, who were considered to be at Level 3 on the BRAT-J, scored higher than the cutoff point (>10) for the detection of depressive disorder. On the other hand, one-third of the individuals, who were considered to be at Level 2 on the BRAT-J, scored higher than the cutoff point. Therefore, it appears that the BRAT-J can predict the likelihood of difficulties or complications in bereaved family caregivers. This research was approved by the Ethics Committee of Tohoku University Graduate School of Medicine and Tohoku University Hospital.

Keywords: palliative care, family caregivers, bereavement risk, BRAT, post-loss psychological distress

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Authors: Sarah K. Hagi, Majdi Alnowaimi

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In the last decade, there were immense advancements in the medical imaging modalities. These advancements can scan a whole volume of the lung organ in high resolution images within a short time. According to this performance, the physicians can clearly identify the complicated anatomical and pathological structures of lung. Therefore, these advancements give large opportunities for more advance of all types of lung cancer treatment available and will increase the survival rate. However, lung cancer is still one of the major causes of death with around 19% of all the cancer patients. Several factors may affect survival rate. One of the serious effects is the breathing process, which can affect the accuracy of diagnosis and lung tumor treatment plan. We have therefore developed a semi automated algorithm to localize the 3D lung tumor positions across all respiratory data during respiratory motion. The algorithm can be divided into two stages. First, a lung tumor segmentation for the first phase of the 4D computed tomography (CT). Lung tumor segmentation is performed using an active contours method. Then, localize the tumor 3D position across all next phases using a 12 degrees of freedom of an affine transformation. Two data set where used in this study, a compute simulate for 4D CT using extended cardiac-torso (XCAT) phantom and 4D CT clinical data sets. The result and error calculation is presented as root mean square error (RMSE). The average error in data sets is 0.94 mm ± 0.36. Finally, evaluation and quantitative comparison of the results with a state-of-the-art registration algorithm was introduced. The results obtained from the proposed localization algorithm show a promising result to localize alung tumor in 4D CT data.

Keywords: automated algorithm , computed tomography, lung tumor, tumor localization

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Authors: Aoxue Yang, Weili Tian, Yonghe Wu, Haikun Liu

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Brain tumor stem cells (BTSCs) are resistant to therapy and give rise to recurrent tumors. These rare and elusive cells are likely to disseminate during cancer progression, and some may enter dormancy, remaining viable but not increasing. The identification of dormant BTSCs is thus necessary to design effective therapies for glioblastoma (GBM) patients. Little progress has been made in therapeutic treatment of glioblastoma in the last decade despite rapid progress in molecular understanding of brain tumors1. Here we show that the stress hormone glucocorticoid is essential for the maintenance of brain tumor stem cells (BTSCs), which are resistant to conventional therapy. The glucocorticoid receptor (GR) regulates metabolic plasticity and chemoresistance of the dormant BTSC via controlling expression of GPD1 (glycerol-3-phosphate dehydrogenase 1), which is an essential regulator of lipid metabolism in BTSCs. Genomic, lipidomic and cellular analysis confirm that GR/GPD1 regulation is essential for BTSCs metabolic plasticity and survival. We further demonstrate that the GR agonist dexamethasone (DEXA), which is commonly used to control edema in glioblastoma, abolishes the effect of chemotherapy drug temozolomide (TMZ) by upregulating GPD1 and thus promoting tumor cell dormancy in vivo, this provides a mechanistic explanation and thus settle the long-standing debate of usage of steroid in brain tumor patient edema control. Pharmacological inhibition of GR/GPD1 pathway disrupts metabolic plasticity of BTSCs and prolong animal survival, which is superior to standard chemotherapy. Patient case study shows that GR antagonist mifepristone blocks tumor progression and leads to symptomatic improvement. This study identifies an important mechanism regulating cancer stem cell dormancy and provides a new opportunity for glioblastoma treatment.

Keywords: cancer stem cell, dormancy, glioblastoma, glycerol-3-phosphate dehydrogenase 1, glucocorticoid receptor, dexamethasone, RNA-sequencing, phosphoglycerides.

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Authors: Ripon Sarkar, Kabita Chaterjee, Ananya Barui

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Smoking is one of the leading causes of oral cancer. Cigarette smoke affects various cellular parameters and alters molecular metabolism of cells. Epithelial cells losses their cytoskeleton structure, membrane integrity, cellular polarity that subsequently initiates the process of epithelial cells to mesenchymal transition due to long exposure of cigarette smoking. It changes the normal cellular metabolic activity which induces oxidative stress and enhances the reactive oxygen spices (ROS) formation. Excessive ROS and associated oxidative stress are considered to be a driving force in alteration in cellular phenotypes, polarity distribution and mitochondrial metabolism. Noninvasive assessment of such parameters plays essential role in development of routine screening system for early diagnosis of oral cancer. Electrical cell-substrate impedance sensing (ECIS) is one of such method applied for detection of cellular membrane impedance which can be correlated to cell membrane integrity. Present study intends to explore the alteration in cellular impedance along with the expression of cellular polarity molecules and cytoskeleton distributions in oral epithelial cells of habitual smokers and to correlate the outcome to that of clinically diagnosed oral leukoplakia and oral squamous cell carcinoma patients. Total 80 subjects were categorized into four study groups: nonsmoker (NS), cigarette smoker (CS), oral leukoplakia (OLPK) and oral squamous cell carcinoma (OSCC). Cytoskeleton distribution was analyzed by staining of actin filament and generation of ROS was measured using assay kit using standard protocol. Cell impedance was measured through ECIS method at different frequencies. Expression of E-cadherin and protease-activated receptor (PAR) proteins were observed through immune-fluorescence method. Distribution of actin filament is well organized in NS group however; distribution pattern was grossly varied in CS, OLPK and OSCC. Generation of ROS was low in NS which subsequently increased towards OSCC. Expressions of E-cadherin and change in cellular electrical impedance in different study groups indicated the hallmark of cancer progression from NS to OSCC. Expressions of E-cadherin, PAR protein, and cell impedance were decreased from NS to CS and farther OSCC. Generally, the oral epithelial cells exhibit apico-basal polarity however with cancer progression these cells lose their characteristic polarity distribution. In this study expression of polarity molecule and ECIS observation indicates such altered pattern of polarity among smoker group. Overall the present study monitored the alterations in intracellular ROS generation and cell metabolic function, membrane integrity in oral epithelial cells in cigarette smokers. Present study thus has clinical significance, and it may help in developing a noninvasive technique for early diagnosis of oral cancer amongst susceptible individuals.

Keywords: cigarette smoking, early oral cancer detection, electric cell-substrate impedance sensing, noninvasive screening

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Authors: Amanina Iymia Jeffree, Reena Thriumani, Mohammad Iqbal Omar, Ammar Zakaria, Yumi Zuhanis Has-Yun Hashim, Ali Yeon Md Shakaff

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Metabolite profiling is a strategy to be approached in the pattern recognition method focused on three types of cancer cell line that driving the most to death specifically lung, breast, and colon cancer. The purpose of this study was to discriminate the VOCs pattern among cancerous and control group based on metabolite profiling. The sampling was executed utilizing the cell culture technique. All culture flasks were incubated till 72 hours and data collection started after 24 hours. Every running sample took 24 minutes to be completed accordingly. The comparative metabolite patterns were identified by the implementation of headspace-solid phase micro-extraction (HS-SPME) sampling coupled with gas chromatography-mass spectrometry (GCMS). The optimizations of the main experimental variables such as oven temperature and time were evaluated by response surface methodology (RSM) to get the optimal condition. Volatiles were acknowledged through the National Institute of Standards and Technology (NIST) mass spectral database and retention time libraries. To improve the reliability of significance, it is of crucial importance to eliminate background noise which data from 3rd minutes to 17th minutes were selected for statistical analysis. Targeted metabolites, of which were annotated as known compounds with the peak area greater than 0.5 percent were highlighted and subsequently treated statistically. Volatiles produced contain hundreds to thousands of compounds; therefore, it will be optimized by chemometric analysis, such as principal component analysis (PCA) as a preliminary analysis before subjected to a pattern classifier for identification of VOC samples. The volatile organic compound profiling has shown to be significantly distinguished among cancerous and control group based on metabolite profiling.

Keywords: in vitro cancer cell line, metabolite profiling, pattern recognition, volatile organic compounds

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Authors: Nurkhairul Bariyah Baharun, Afzan Adam, Reena Rahayu Md Zin

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Tumor microenvironment (TME) in breast cancer is mainly composed of cancer cells, immune cells, and stromal cells. The interaction between cancer cells and their microenvironment plays an important role in tumor development, progression, and treatment response. The TME in breast cancer includes tumor-infiltrating lymphocytes (TILs) that are implicated in killing tumor cells. TILs can be found in tumor stroma (sTILs) and within the tumor (iTILs). TILs in triple negative breast cancer (TNBC) have been demonstrated to have prognostic and potentially predictive value. The international Immune-Oncology Biomarker Working Group (TIL-WG) had developed a guideline focus on the assessment of sTILs using hematoxylin and eosin (H&E)-stained slides. According to the guideline, the pathologists use “eye balling” method on the H&E stained- slide for sTILs assessment. This method has low precision, poor interobserver reproducibility, and is time-consuming for a comprehensive evaluation, besides only counted sTILs in their assessment. The TIL-WG has therefore recommended that any algorithm for computational assessment of TILs utilizing the guidelines provided to overcome the limitations of manual assessment, thus providing highly accurate and reliable TILs detection and classification for reproducible and quantitative measurement. This study is carried out to develop a TNBC digital whole slide image (WSI) dataset from H&E-stained slides and IHC (CD4+ and CD8+) stained slides. TNBC cases were retrieved from the database of the Department of Pathology, Hospital Canselor Tuanku Muhriz (HCTM). TNBC cases diagnosed between the year 2010 and 2021 with no history of other cancer and available block tissue were included in the study (n=58). Tissue blocks were sectioned approximately 4 µm for H&E and IHC stain. The H&E staining was performed according to a well-established protocol. Indirect IHC stain was also performed on the tissue sections using protocol from Diagnostic BioSystems PolyVue™ Plus Kit, USA. The slides were stained with rabbit monoclonal, CD8 antibody (SP16) and Rabbit monoclonal, CD4 antibody (EP204). The selected and quality-checked slides were then scanned using a high-resolution whole slide scanner (Pannoramic DESK II DW- slide scanner) to digitalize the tissue image with a pixel resolution of 20x magnification. A manual TILs (sTILs and iTILs) assessment was then carried out by the appointed pathologist (2 pathologists) for manual TILs scoring from the digital WSIs following the guideline developed by TIL-WG 2014, and the result displayed as the percentage of sTILs and iTILs per mm² stromal and tumour area on the tissue. Following this, we aimed to develop an automated digital image scoring framework that incorporates key elements of manual guidelines (including both sTILs and iTILs) using manually annotated data for robust and objective quantification of TILs in TNBC. From the study, we have developed a digital dataset of TNBC H&E and IHC (CD4+ and CD8+) stained slides. We hope that an automated based scoring method can provide quantitative and interpretable TILs scoring, which correlates with the manual pathologist-derived sTILs and iTILs scoring and thus has potential prognostic implications.

Keywords: automated quantification, digital pathology, triple negative breast cancer, tumour infiltrating lymphocytes

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Authors: Anas Al-Ali, Mohammed Suleiman, Ayman Hussein

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Sulfur is an important element has many practical applications in present as nanoparticles. Nanosize sulfur particles also have many important applications like in pharmaceuticals, medicine, syn-thesis of nano-composites for lithium batteries, modification of carbon nano tubes. Different methods were used for nano-sized particle synthesis; among those, chemical precipitation, electrochemical method, micro emulsion technique, composing of oil, surfactant, co-surfactant, aqueous phases with the specific compositions and ultrasonic treatment of sulfur-cystine solution. In this work Sulfur nanoparticles (S NPs) were prepared by a quick precipitation method with and without using a surfactant to stabilize the formed S NPs. The synthesized S NPs were characterized by XRD, SEM and TEM in order to confirm their sizes and structures.Application of nanotechnology is suggested for diag-nosis and treatment of cancer. The anticancer activity of the prepared S NPs has been tested on various types of cancer cell clones including leukemia, kidney and colon cancers.

Keywords: sulfur nanoparticles (S-NPs), TEM, SEM, XRD

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Authors: B. Petrović, M. Petrović, L. Rutonjski, I. Djan, V. Ivanović

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Objective: Cardiac pacemakers are very sensitive to radiotherapy treatment from two sources: electromagnetic influence from the medical linear accelerator producing ionizing radiation- influencing electronics within the pacemaker, and the absorption of dose to the device. On the other hand, patients with cardiac pacemakers at the place of a tumor are rather rare, and single clinic hardly has experience with the management of such patients. The widely accepted international guidelines for management of radiation oncology patients recommend that these patients should be closely monitored and examined before, during and after radiotherapy treatment by cardiologist, and their device and condition followed up. The number of patients having both cancer and pacemaker, is growing every year, as both cancer incidence, as well as cardiac diseases incidence, are inevitably growing figures. Materials and methods: Female patient, age 69, was diagnozed with valvular cardiomyopathy and got implanted a pacemaker in 2005 and prosthetic mitral valve in 1993 (cancer was diagnosed in 2012). She was stable cardiologically and came to radiation therapy department with the diagnosis of right breast cancer, with the tumor in upper lateral quadrant of the right breast. Since she had all lymph nodes positive (28 in total), she had to have irradiated the supraclavicular region, as well as the breast with the tumor bed. She previously received chemotherapy, approved by the cardiologist. The patient was estimated to be with the high risk as device was within the field of irradiation, and the patient had high dependence on her pacemaker. The radiation therapy plan was conducted as 3D conformal therapy. The delineated target was breast with supraclavicular region, where the pacemaker was actually placed, with the addition of a pacemaker as organ at risk, to estimate the dose to the device and its components as recommended, and the breast. The targets received both 50 Gy in 25 fractions (where 20% of a pacemaker received 50 Gy, and 60% of a device received 40 Gy). The electrode to the heart received between 1 Gy and 50 Gy. Verification of dose planned and delivered was performed. Results: Evaluation of the patient status according to the guidelines and especially evaluation of all associated risks to the patient during treatment was done. Patient was irradiated by prescribed dose and followed up for the whole year, with no symptoms of failure of the pacemaker device during, or after treatment in follow up period. The functionality of a device was estimated to be unchanged, according to the parameters (electrode impedance and battery energy). Conclusion: Patient was closely monitored according to published guidelines during irradiation and afterwards. Pacemaker irradiated with the full dose did not show any signs of failure despite recommendations data, but in correlation with other published data.

Keywords: cardiac pacemaker, breast cancer, radiotherapy treatment planning, complications of treatment

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Authors: Kim Kennedy, Daren Gibson, Stephanie Flukes, Chandra Diwakarla, Lisa Spalding, Leanne Pilkington, Andrew Redfern

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Introduction: Head and neck cancers (HNC) are often associated with the development of non-HNC primaries, as the risk factors that predispose patients to HNC are often risk factors for other cancers. Aim: We sought to evaluate whether there was an increased risk of smoking and alcohol-related cancers and also other cancers in HNC patients and to evaluate whether there is a difference between the rates of non-HNC primaries in Aboriginal compared with non-Aboriginal HNC patients. Methods: We performed a retrospective cohort analysis of 320 HNC patients from a single center in Western Australia, identifying 80 Aboriginal and 240 non-Aboriginal patients matched on a 1:3 ratio by sites, histology, rurality, and age. We collected data on the patient characteristics, tumour features, treatments, outcomes, and past and subsequent HNCs and non-HNC primaries. Results: In the overall study population, there were 86 patients (26.9%) with a metachronous or synchronous non-HNC primary. Non-HNC primaries were actually significantly more common in the non-Aboriginal population compared with the Aboriginal population (30% vs. 17.5%, p=0.02); however, half of these were patients with cutaneous squamous or basal cell carcinomas (cSCC/BCC) only. When cSCC/BCCs were excluded, non-Aboriginal patients had a similar rate as Aboriginal patients (16.7% vs. 15%, p=0.73). There were clearly more cSCC/BCCs in non-Aboriginal patients compared with Aboriginal patients (16.7% vs. 2.5%, p=0.001) and more patients with melanoma (2.5% vs. 0%, p value not significant (p=NS). Rates of most cancers were similar between non-Aboriginal and Aboriginal patients, including prostate (2.9% vs. 3.8%), colorectal (2.9% vs. 2.5%), kidney (1.2% vs. 1.2%), and these rates appeared comparable to Australian Age Standardised Incidence Rates (ASIR) in the general community. Oesophageal cancer occurred at double the rate in Aboriginal patients (3.8%) compared with non-Aboriginal patients (1.7%), which was far in excess of ASIRs which estimated a lifetime risk of 0.59% in the general population. Interestingly lung cancer rates did not appear to be significantly increased in our cohort, with 2.5% of Aboriginal patients and 3.3% of non-Aboriginal patients having lung cancer, which is in line with ASIRs which estimates a lifetime risk of 5% (by age 85yo). Interestingly the rate of Glioma in the non-Aboriginal population was higher than the ASIR, with 0.8% of non-Aboriginal patients developing Glioma, with Australian averages predicting a 0.6% lifetime risk in the general population. As these are small numbers, this finding may well be due to chance. Unsurprisingly, second HNCs occurred at an increased incidence in our cohort, in 12.5% of Aboriginal patients and 11.2% of non-Aboriginal patients, compared to an ASIR of 17 cases per 100,000 persons, estimating a lifetime risk of 1.70%. Conclusions: Overall, 26.9% of patients had a non-HNC primary. When cSCC/BCCs were excluded, Aboriginal and non-Aboriginal patients had similar rates of non-HNC primaries, although non-Aboriginal patients had a significantly higher rate of cSCC/BCCs. Aboriginal patients had double the rate of oesophageal primaries; however, this was not statistically significant, possibly due to small case numbers.

Keywords: head and neck cancer, synchronous and metachronous primaries, other primaries, Aboriginal

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Authors: Soumya Sajjan

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Liver cancer is the most common cancer disease worldwide in men and women, and is one of the few cancers still on the rise. Liver disease is the 4th leading cause of death. According to new NHS (National Health Service) figures, deaths from liver diseases have reached record levels, rising by 25% in less than a decade; heavy drinking, obesity, and hepatitis are believed to be behind the rise. In this study, we focus on Development of Diagnostic Classifier for Ultrasound liver lesion. Ultrasound (US) Sonography is an easy-to-use and widely popular imaging modality because of its ability to visualize many human soft tissues/organs without any harmful effect. This paper will provide an overview of underlying concepts, along with algorithms for processing of liver ultrasound images Naturaly, Ultrasound liver lesion images are having more spackle noise. Developing classifier for ultrasound liver lesion image is a challenging task. We approach fully automatic machine learning system for developing this classifier. First, we segment the liver image by calculating the textural features from co-occurrence matrix and run length method. For classification, Support Vector Machine is used based on the risk bounds of statistical learning theory. The textural features for different features methods are given as input to the SVM individually. Performance analysis train and test datasets carried out separately using SVM Model. Whenever an ultrasonic liver lesion image is given to the SVM classifier system, the features are calculated, classified, as normal and diseased liver lesion. We hope the result will be helpful to the physician to identify the liver cancer in non-invasive method.

Keywords: segmentation, Support Vector Machine, ultrasound liver lesion, co-occurance Matrix

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Authors: Vanitha Varadharaj, Vijalakshmi Krishnamurthy

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Annona squamosa Linn, commonly known as Sugar apple, belonging to the family Annonaceae, is said to show varied medicinal effects, including insecticide, antiovulatory and abortifacient. The alkaloid and flavonoids present in Annona squamosa leaf has proved to have antioxidant activity. The present work has been planned to investigate the effect of ethanolic leaf extract of Annona squamosa leaf on Den Induced wistar albino rats. The study was carried out to analyze the biochemical Parmeters like Total Proteins, Bilirubin, Enzymatic and Non –Enzymatic enzymes, Marker enzymes and Tumor markers in serum and also the histopathological studies in liver is carried out in control and DEN induced rats. Supplementation of ELAS (Ethanolic Leaf Extract Of Annona squamosa) reduced the liver weight and also reduced the tumour incidence. Chemoprevention group showed near normal values of bilirubin when compared with the control rats. Total protein was decreased in the cancer bearing group and on treatment with the extract the levels of protein were restored. Both in pre and post treatment group, the activities of enzymatic antioxidants such as superoxide dismutase, catalase, and Glutathione peroxidase were increased but in pre treated animals it was more effective than post treated animals. The non- enzymatic antioxidants such as vitamin C and vitamin E were brought back to normal level significantly in post and pre treated animals. Activities of marker enzymes such as SGOT, SGPT, ALP, γ GT were significantly elevated in the serum of cancer animals and the values returned to normal after treatment with the extract suggesting the hepato protective effect of the extract. Lipid peroxide was found to be elevated in the cancer induced group. This condition was brought back to the normal in the pre and post treated animals with ELAS. Histological examination also confirmed the anti- carcinogenic potential of ELAS, Cancer induced groups had a triple fold increase in their AFP values when compared to other groups. DEN treatment increased the level of AFP expression while ELAS partially counteracted the effect of it. So the scientific validation obtained from this study may pave way to many budding scientists to find new drugs from Annona squamosa for various ailments.

Keywords: annona squamosa, biochemical parmeters, cancer, leaf extract

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Authors: Małgorzata Drzewiecka, Tomasz Śliwiński, Maciej Radek

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The inhibition of histone deacetyles (HDACs) holds promise as a potential anti-cancer therapy because histone and non-histone protein acetylation is frequently disrupted in cancer, leading to cancer initiation and progression. Additionally, histone deacetylase inhibitors (HDACi) such as class I HDAC inhibitor - valproic acid (VPA) have been shown to enhance the effectiveness of DNA-damaging factors, such as cisplatin or radiation. In this study, we found that, using of VPA in combination with talazoparib (BMN-637 – PARP1 inhibitor – PARPi) and/or Dacarabazine (DTIC - alkylating agent) resulted in increased DNA double strand break (DSB) and reduced survival (while not affecting primary melanocytes )and proliferation of melanoma cells. Furthermore, pharmacologic inhibition of class I HDACs sensitizes melanoma cells to apoptosis following exposure to DTIC and BMN-637. In addition, inhibition of HDAC caused sensitization of melanoma cells to dacarbazine and BMN-637 in melanoma xenografts in vivo. At the mRNA and protein level histone deacetylase inhibitor downregulated RAD51 and FANCD2. This study provides that combining HDACi, alkylating agent and PARPi could potentially enhance the treatment of melanoma, which is known for being one of the most aggressive malignant tumors. The findings presented here point to a scenario in which HDAC via enhancing the HR-dependent repair of DSBs created during the processing of DNA lesions, are essential nodes in the resistance of malignant melanoma cells to methylating agent-based therapies.

Keywords: melanoma, hdac, parp inhibitor, valproic acid

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Authors: Godwin Dennison, C. E. Boulind, O. Gould, B. de Lacy Costello, J. Allison, P. White, P. Ewings, A. Wicaksono, N. J. Curtis, A. Pullyblank, D. Jayne, J. A. Covington, N. Ratcliffe, N. K. Francis

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Background: Colorectal symptoms are common but only infrequently represent serious pathology, including colorectal cancer (CRC). A large number of invasive tests are presently performed for reassurance. We investigated the feasibility of urinary volatile organic compound (VOC) testing as a potential triage tool in patients fast-tracked for assessment for possible CRC. Methods: A prospective, multi-centre, observational feasibility study was performed across three sites. Patients referred on NHS fast-track pathways for potential CRC provided a urine sample which underwent Gas Chromatography Mass Spectrometry (GC-MS), Field Asymmetric Ion Mobility Spectrometry (FAIMS) and Selected Ion Flow Tube Mass Spectrometry (SIFT-MS) analysis. Patients underwent colonoscopy and/or CT colonography and were grouped as either CRC, adenomatous polyp(s), or controls to explore the diagnostic accuracy of VOC output data supported by an artificial neural network (ANN) model. Results: 558 patients participated with 23 (4.1%) CRC diagnosed. 59% of colonoscopies and 86% of CT colonographies showed no abnormalities. Urinary VOC testing was feasible, acceptable to patients, and applicable within the clinical fast track pathway. GC-MS showed the highest clinical utility for CRC and polyp detection vs. controls (sensitivity=0.878, specificity=0.882, AUROC=0.884). Conclusion: Urinary VOC testing and analysis are feasible within NHS fast-track CRC pathways. Clinically meaningful differences between patients with cancer, polyps, or no pathology were identified therefore suggesting VOC analysis may have future utility as a triage tool. Acknowledgment: Funding: NIHR Research for Patient Benefit grant (ref: PB-PG-0416-20022).

Keywords: colorectal cancer, volatile organic compound, gas chromatography mass spectrometry, field asymmetric ion mobility spectrometry, selected ion flow tube mass spectrometry

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Authors: Z. Kolacinski, L. Szymanski. G. Raniszewski, D. Koza, L. Pietrzak

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Magnetic Bio-Nano-Fluid (BNF) can be composed of a buffer fluid such as plasma and magnetic nanoparticles such as iron, nickel, cobalt and their oxides. However iron is one of the best elements for magnetization by electromagnetic radiation. It can be used as a tool for medical diagnosis and treatment. Radio frequency (RF) radiation is able to heat iron nanoparticles due to magnetic hysteresis. Electromagnetic heating of iron nanoparticles and ferro-fluids BNF can be successfully used for non-invasive thermal ablation of cancer cells. Moreover iron atoms can be carried by carbon nanotubes (CNTs) if iron is used as catalyst for CNTs synthesis. Then CNTs became the iron containers and they screen the iron content against oxidation. We will present a method of CNTs addressing to the required cells. For thermal ablation of cancer cells we use radio frequencies for which the interaction with human body should be limited to minimum. Generally, the application of RF energy fields for medical treatment is justified by deep tissue penetration. The highly iron doped CNTs as the carriers creating magnetic fluid will be presented. An excessive catalyst injection method using electrical furnace and microwave plasma reactor will be presented. This way it is possible to grow the Fe filled CNTs on a moving surface in continuous synthesis process. This also allows producing uniform carpet of the Fe filled CNTs carriers. For the experimental work targeted to cell ablation we used RF generator to measure the increase in temperature for some samples like: solution of Fe2O3 in BNF which can be plasma-like buffer, solutions of pure iron of different concentrations in plasma-like buffer and in buffer used for a cell culture, solutions of carbon nanotubes (MWCNTs) of different concentrations in plasma-like buffer and in buffer used for a cell culture. Then the targeted therapies which can be effective if the carriers are able to distinguish the difference between cancerous and healthy cell’s physiology are considered. We have developed an approach based on ligand-receptor or antibody-antigen interactions for the case of colon cancer.

Keywords: cancer treatment, carbon nano tubes, drag delivery, hyperthermia, iron

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Authors: Fadzil Ahmad, Noor Ashidi Mat Isa

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This study introduces an improved genetic algorithm procedure that focuses search around near optimal solution corresponded to a group of elite chromosome. This is achieved through a novel crossover technique known as Segmented Multi Chromosome Crossover. It preserves the highly important information contained in a gene segment of elite chromosome and allows an offspring to carry information from gene segment of multiple chromosomes. In this way the algorithm has better possibility to effectively explore the solution space. The improved GA is applied for the automatic and simultaneous parameter optimization and feature selection of artificial neural network in pattern recognition of medical problem, the cancer and diabetes disease. The experimental result shows that the average classification accuracy of the cancer and diabetes dataset has improved by 0.1% and 0.3% respectively using the new algorithm.

Keywords: genetic algorithm, artificial neural network, pattern clasification, classification accuracy

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Authors: Heeba A. Gurku

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Introduction: Cone Beam CT(CBCT) images play an integral part in proper patient positioning in cancer patients undergoing radiation therapy treatment. But these images are low in quality. The purpose of this study is to generate high-quality synthetic CT images from CBCT using generative models. Material and Methods: This study utilized two datasets from The Cancer Imaging Archive (TCIA) 1) Lung cancer dataset of 20 patients (with full view CBCT images) and 2) Pancreatic cancer dataset of 40 patients (only 27 patients having limited view images were included in the study). Cycle Generative Adversarial Networks (GAN) and its variant Attention Guided Generative Adversarial Networks (AGGAN) models were used to generate the synthetic CTs. Models were evaluated by visual evaluation and on four metrics, Structural Similarity Index Measure (SSIM), Peak Signal Noise Ratio (PSNR) Mean Absolute Error (MAE) and Root Mean Square Error (RMSE), to compare the synthetic CT and original CT images. Results: For pancreatic dataset with limited view CBCT images, our study showed that in Cycle GAN model, MAE, RMSE, PSNR improved from 12.57to 8.49, 20.94 to 15.29 and 21.85 to 24.63, respectively but structural similarity only marginally increased from 0.78 to 0.79. Similar, results were achieved with AGGAN with no improvement over Cycle GAN. However, for lung dataset with full view CBCT images Cycle GAN was able to reduce MAE significantly from 89.44 to 15.11 and AGGAN was able to reduce it to 19.77. Similarly, RMSE was also decreased from 92.68 to 23.50 in Cycle GAN and to 29.02 in AGGAN. SSIM and PSNR also improved significantly from 0.17 to 0.59 and from 8.81 to 21.06 in Cycle GAN respectively while in AGGAN SSIM increased to 0.52 and PSNR increased to 19.31. In both datasets, GAN models were able to reduce artifacts, reduce noise, have better resolution, and better contrast enhancement. Conclusion and Recommendation: Both Cycle GAN and AGGAN were significantly able to reduce MAE, RMSE and PSNR in both datasets. However, full view lung dataset showed more improvement in SSIM and image quality than limited view pancreatic dataset.

Keywords: CT images, CBCT images, cycle GAN, AGGAN

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Authors: Nusrat Masood, Vijaya Dubey, Suaib Luqman

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Caspase 3, a member of cysteine-aspartic acid protease family, is an imperative indicator for cell death particularly when substantiating apoptosis. Thus, caspase 3 is an interesting target for the discovery and development of anticancer agent. We adopted a four level assessment of both terpenoids and flavonoids and thus experimentally performed the enzymatic assay in cell free system as well as in cancer cell line which was validated through real time expression and molecular interaction studies. A significant difference was observed with both the class of natural products indicating terpenoids as better activators of caspase 3 compared to flavonoids both in the cell free system as well as in cell lines. The expression analysis, activation constant and binding energy also correlate well with the enzyme activity. Overall, terpenoids had an unswerving effect on caspase 3 in all the tested system while flavonoids indirectly affect enzyme activity.

Keywords: Caspase 3, terpenoids, flavonoids, activation constant, binding energy

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Authors: Seyhan Karaçavuş, Bülent Yılmaz, Ömer Kayaaltı, Semra İçer, Arzu Taşdemir, Oğuzhan Ayyıldız, Kübra Eset, Eser Kaya

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In this study, our goal was to perform tumor staging and subtype determination automatically using different texture analysis approaches for a very common cancer type, i.e., non-small cell lung carcinoma (NSCLC). Especially, we introduced a texture analysis approach, called Law’s texture filter, to be used in this context for the first time. The 18F-FDG PET images of 42 patients with NSCLC were evaluated. The number of patients for each tumor stage, i.e., I-II, III or IV, was 14. The patients had ~45% adenocarcinoma (ADC) and ~55% squamous cell carcinoma (SqCCs). MATLAB technical computing language was employed in the extraction of 51 features by using first order statistics (FOS), gray-level co-occurrence matrix (GLCM), gray-level run-length matrix (GLRLM), and Laws’ texture filters. The feature selection method employed was the sequential forward selection (SFS). Selected textural features were used in the automatic classification by k-nearest neighbors (k-NN) and support vector machines (SVM). In the automatic classification of tumor stage, the accuracy was approximately 59.5% with k-NN classifier (k=3) and 69% with SVM (with one versus one paradigm), using 5 features. In the automatic classification of tumor subtype, the accuracy was around 92.7% with SVM one vs. one. Texture analysis of FDG-PET images might be used, in addition to metabolic parameters as an objective tool to assess tumor histopathological characteristics and in automatic classification of tumor stage and subtype.

Keywords: cancer stage, cancer cell type, non-small cell lung carcinoma, PET, texture analysis

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Authors: Dipranjan Laha, Parimal Karmakar

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Metal oxide nanoparticles are well known to generate oxidative stress and deregulate normal cellular activities. Among these, transition metals copper oxide nanoparticles (CuO NPs) are more compelling than others and able to modulate different cellular responses. In this work, we have synthesized and characterized CuO NPs by various biophysical methods. These CuO NPs (~30 nm) induce autophagy in human breast cancer cell line, MCF7 in a time and dose-dependent manner. Cellular autophagy was tested by MDC staining, induction of green fluorescent protein light chain 3 (GFP-LC3B) foci by confocal microscopy, transfection of pBABE-puro mCherry-EGFP-LC3B plasmid and western blotting of autophagy marker proteins LC3B, beclin1, and ATG5. Further, inhibition of autophagy by 3-Methyladenine (3-MA) decreased LD50 doses of CuO NPs. Such cell death was associated with the induction of apoptosis as revealed by FACS analysis, cleavage of PARP, dephosphorylation of Bad and increased cleavage product of caspase3. siRNA-mediated inhibition of autophagy-related gene beclin1 also demonstrated similar results. Finally, induction of apoptosis by 3-MA in CuO NPs treated cells were observed by TEM. This study indicates that CuO NPs are a potent inducer of autophagy which may be a cellular defense against the CuO NPs mediated toxicity and inhibition of autophagy switches the cellular response into apoptosis. A combination of CuO NPs with the autophagy inhibitor is essential to induce apoptosis in breast cancer cells. Acknowledgments: The authors would like to acknowledge for financial support for this research work to the Department of Biotechnology (No. BT/PR14661/NNT/28/494/2010), Government of India.

Keywords: nanoparticle, autophagy, apoptosis, siRNA-mediated inhibition

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Authors: John Joseph S. Martis, Rohanchandra R. Gatty, Aaron Jose Fernandes, Rahul P. Nambiar

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Introduction: Surgery for breast cancer is either mastectomy or breast conservation surgery. The most commonly used incision for modified radical mastectomy is the transverse Stewart incision. But this incision may have the disadvantage of causing disparity between the closure lines of superior and inferior skin flaps in mastectomy and can cause overhanging of soft tissue below and behind the axilla. The curvizigzag incision, on principle, may help in this regard and can prevent scar migration beyond the anterior axillary line. This study aims to compare the two incisions in this regard. Methods: 100 patients with cancer of breast were included in the study after satisfying inclusion and exclusion criteria. They underwent surgery at Father Muller Medical College, Mangalore, India, between November 2019 to September 2021. The patients were divided into two groups. Group A patients were subjected to modified radical mastectomy with curvizigzag incision and group B patients with transverse Stewart incision. Results: Seroma on postoperative day1, day 2 was 0% in both the groups. Seroma on postoperative day 30 was present in 14% of patients in group B. 60% of patients in group B had sag of soft tissue below and behind the axilla, and none of the patients in group A had this problem. In 64% of the patients in group B, the incision crossed the anterior axillary fold, 64% of the patients in group B had tension in the incision site while approximation of the skin flaps. Conclusion: Curvizigzag incision is statistically better with lesser complications when compared to the transverse Stewart incision for modified radical mastectomy for carcinoma breast.

Keywords: breast cancer, curvizigzag incision, transverse Stewart incision, seroma, modified radical mastectomy

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Authors: Michio Kurosu

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Alterations in glycosylation not only directly impact cell growth and survival but also facilitate tumor-induced immunomodulation and eventual metastasis. Identification of cell type-specific glycoconjugates (tumor markers) has led to the discovery of new assay systems for certain cancers via immunodetection reagents. N- and O-linked glycans are the most abundant forms of glycoproteins. Recent studies of cancer immunotherapy are based on the immunogenicity of truncated O-glycan chains (e.g., Tn, sTn, T, and sLea/x). The prevalence of N-linked glycan changes in the development of tumor cells is known; however, therapeutic antibodies against N-glycans have not yet been developed. This is due to the lack of specificity of N-linked glycans between normal/healthy and cancer cells. Abnormal branching of N-linked glycans has been observed, particularly in solid cancer cells. While the discovery of drug-like glycosyltransferase inhibitors that block the biosynthesis of specific branching has a very low likelihood of success, altered glycosylation levels can be exploited by suppressing N-glycan biosynthesis through the inhibition of dolichyl-phosphate N-acetylglucosaminephosphotransferase1 (DPAGT1) activity. Inhibition of DPAGT1 function leads to changes of O-glycosylation on proteins associated with mitochondria and zinc finger binding proteins (indirect effects). On the basis of dynamic crosstalk between DPAGT1 and Snail/Slung/ZEB1 (a family of transcription factors that promote the repression of the adhesion molecules), we have developed pharmacologically acceptable selective DPAGT1 inhibitors. Tunicamycin kills a wide range of cancer and healthy cells in a non-selective manner. In sharp contrast, our DPAGT1 inhibitors display strong cytostatic effects against 16 solid cancers, which require the overexpression of DPAGT1 in their progression but do not affect the cell viability of healthy cells. The identified DPAGT1 inhibitors possess impressive anti-metastatic ability in various solid cancer cell lines and induce their mitochondrial structural changes, resulting in apoptosis. A prototype DPAGT1 inhibitor, APPB has already been proven to shrink solid tumors (e.g., pancreatic cancers, triple-negative breast cancers) in vivo while suppressing metastases and has strong synergistic effects when combined with current cytotoxic drugs (e.g., paclitaxel). At this conference, our discovery of selective DPAGT1 inhibitors with drug-like properties and proof-of-pharmaceutical concept studies of a novel DPAGT1 inhibitor are presented.

Keywords: DPAGT1 inhibitors, anti-metastatic drugs, natural product based drug designs, cytostatic effects

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Authors: S. Pradhan, D. Pradhan, G. Tripathy

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Anti-estrogen treatment resistant is a noteworthy reason for disease relapse and mortality in estrogen receptor alpha (ERα)- positive breast cancers. Tamoxifen or estrogen withdrawal increases the dependance of breast malignancy cells on INT3 signaling. Here, we researched the contribution of Quercetin and INT3 signaling in endocrine resistant breast cancer cells. Methods: We utilized two models of endocrine therapies resistant (ETR-) breast cancer: tamoxifen-resistant (TamR) and long term estrogen-deprived (LTED) MCF7 cells. We assessed the migratory and invasive limit of these cells by Transwell assay. Expression of epithelial to mesenchymal transition (EMT) controllers and in addition INT3 receptors and targets were assessed by real-time PCR and western blot analysis. Besides, we tried in vitro anti-Quercetin monoclonal antibodies (mAbs) and gamma secretase inhibitors (GSIs) as potential EMT reversal therapeutic agents. At last, we created stable Quercetin over expessing MCF7 cells and assessed their EMT features and response to tamoxifen. Results:We found that ETR cells acquired an epithelial to mesenchymal transition (EMT) phenotype and showed expanded levels of Quercetin and INT3 targets. Interestingly, we detected higher level of INT3 however lower levels of INT31 and INT32 proposing a switch to targeting through distinctive INT3 receptors after obtaining of resistance. Anti-Quercetin monoclonal antibodies and the GSI PF03084014 were effective in obstructing the Quercetin/INT3 axis and in part inhibiting the EMT process. As a consequence of this, cell migration and invasion were weakened and the stem cell like population was considerably decreased. Genetic hushing of Quercetin and INT3 prompted proportionate impacts. Finally, stable overexpression of Quercetin was adequate to make MCF7 lethargic to tamoxifen by INT3 activation. Conclusions: ETR cells express abnormal amounts of Quercetin and INT3, whose actuation eventually drives invasive conduct. Anti-Quercetin mAbs and GSI PF03084014 lessen expression of EMT molecules decreasing cellular invasiveness. Quercetin overexpression instigates tamoxifen resistance connected to obtaining of EMT phenotype. Our discovering propose that focusing on Quercetin and/or INT3 warrants further clinical assessment as substantial therapeutic methodologies in endocrine-resistant breast cancer.

Keywords: quercetin, INT3, mesenchymal transition, MCF7 breast cancer cells

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Authors: Cenza Rhoda, Falone Sunda, Elvis Kidzeru, Nonhlanhla P. Khumalo, Afolake Arowolo

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Introduction: The human FAM111B gene mutations are associated with POIKTMP, a rare multi-organ fibrosing disease. Recent studies also reported the overexpression of FAM111B in specific cancers. However, the role of FAM111B in these pathologies, particularly fibrosarcoma, remains unknown. Materials and Methods: FAM111B RNA expression in some cancer cell lines was assessed in silico and validated in vitro in these cell lines and skin fibroblasts derived from the South African family member affected by POIKTMP with the heterozygous FAM111B gene mutation: NM_198947.4: c.1861T>G (p. Tyr621Asp or Y621D) by qPCR and western blot. The cellular function of FAM111B was also studied in HT1080 using various cell-based functional assays and a simple and cost-effective PCR-RFLP method for genotyping/screening FAM111B gene mutations described. Results: Expression studies showed upregulated FAM111B mRNA and protein in the cancer cells. High FAM111B expression with robust nuclear localization occurred in HT1080. Additionally, expression data and cell-based assays indicated that FAM111B led to the upregulation of cell migration and decreased cell apoptosis and cell proliferation modulation. FAM111B Y621D mutation showed similar effects on cell migration but minimal impact on cell apoptosis. FAM111B mRNA and protein expression were markedly downregulated (p ≤ 0.05) in the patient's skin-derived fibroblasts. Lastly, the PCR-RFLP method successfully genotyped FAM111B Y621D gene mutation. Discussion: FAM111B is a cancer-associated nuclear protein: Its modulation by mutations may enhance cell migration and proliferation and decrease apoptosis, as seen in cancers and POIKTMP/fibrosis, thus representing a viable therapeutic target in these disorders. Furthermore, the PCR-RFLP method could prove a valuable tool for FAM111B mutation validation or screening in resource-constrained laboratories.

Keywords: FAM111B, POIKTMP, cancer, fibrosis, PCR-RFLP

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Authors: Auwal Abubakar, Shazril Imran Shaukat, Noor Khairiah A. Karim, Mohammed Zakir Kassim, Gokula Kumar Appalanaido, Hafiz Mohd Zin

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Background: Voluntary deep inspiration breath-hold radiotherapy (vDIBH-RT) is an effective cardiac dose reduction technique during left breast radiotherapy. This study aimed to assess the accuracy of the implementation of the vDIBH technique among left breast cancer patients without the use of a special device such as a surface-guided imaging system. Methods: The vDIBH-RT technique was implemented among thirteen (13) left breast cancer patients at the Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia. Breath-hold monitoring was performed based on breath-hold skin marks and laser light congruence observed on zoomed CCTV images from the control console during each delivery. The initial setup was verified using cone beam computed tomography (CBCT) during breath-hold. Each field was delivered using multiple beam segments to allow a delivery time of 20 seconds, which can be tolerated by patients in breath-hold. The data were analysed using an in-house developed MATLAB algorithm. PTV margin was computed based on van Herk's margin recipe. Results: The setup error analysed from CBCT shows that the population systematic error in lateral (x), longitudinal (y), and vertical (z) axes was 2.28 mm, 3.35 mm, and 3.10 mm, respectively. Based on the CBCT image guidance, the Planning target volume (PTV) margin that would be required for vDIBH-RT using CCTV/Laser monitoring technique is 7.77 mm, 10.85 mm, and 10.93 mm in x, y, and z axes, respectively. Conclusion: It is feasible to safely implement vDIBH-RT among left breast cancer patients without special equipment. The breath-hold monitoring technique is cost-effective, radiation-free, easy to implement, and allows real-time breath-hold monitoring.

Keywords: vDIBH, cone beam computed tomography, radiotherapy, left breast cancer

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Authors: Swati Srivastava, Mattia Lauriola, Yuval Gilad, Adi Kimchi, Yosef Yarden

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The glucocorticoid receptor (GR) has been proposed to play important, but incompletely understood roles in cancer. Glucocorticoids (GCs) are widely used as co-medication of various carcinomas, due to their ability to reduce the toxicity of chemotherapy. Furthermore, GR antagonism has proven to be a strategy to treat triple negative breast cancer and castration-resistant prostate cancer. These observations suggest differential GR involvement in cancer subtypes. The goal of our study has been to elaborate the current understanding of GR signaling in tumor progression and metastasis. Our study involves two cellular models, non-tumorigenic breast epithelial cells (MCF10A) and Ewing sarcoma cells (CHLA9). In our breast cell model, the results indicated that the GR agonist dexamethasone inhibits EGF-induced mammary cell migration, and this effect was blocked when cells were stimulated with a GR antagonist, namely RU486. Microarray analysis for gene expression revealed that the mechanism underlying inhibition involves dexamenthasone-mediated repression of well-known activators of EGFR signaling, alongside with enhancement of several EGFR’s negative feedback loops. Because GR mainly acts primarily through composite response elements (GREs), or via a tethering mechanism, our next aim has been to find the transcription factors (TFs) which can interact with GR in MCF10A cells.The TF-binding motif overrepresented at the promoter of dexamethasone-regulated genes was predicted by using bioinformatics. To validate the prediction, we performed high-throughput Protein Complementation Assays (PCA). For this, we utilized the Gaussia Luciferase PCA strategy, which enabled analysis of protein-protein interactions between GR and predicted TFs of mammary cells. A library comprising both nuclear receptors (estrogen receptor, mineralocorticoid receptor, GR) and TFs was fused to fragments of GLuc, namely GLuc(1)-X, X-GLuc(1), and X-GLuc(2), where GLuc(1) and GLuc(2) correspond to the N-terminal and C-terminal fragments of the luciferase gene.The resulting library was screened, in human embryonic kidney 293T (HEK293T) cells, for all possible interactions between nuclear receptors and TFs. By screening all of the combinations between TFs and nuclear receptors, we identified several positive interactions, which were strengthened in response to dexamethasone and abolished in response to RU486. Furthermore, the interactions between GR and the candidate TFs were validated by co-immunoprecipitation in MCF10A and in CHLA9 cells. Currently, the roles played by the uncovered interactions are being evaluated in various cellular processes, such as cellular proliferation, migration, and invasion. In conclusion, our assay provides an unbiased network analysis between nuclear receptors and other TFs, which can lead to important insights into transcriptional regulation by nuclear receptors in various diseases, in this case of cancer.

Keywords: epidermal growth factor, glucocorticoid receptor, protein complementation assay, transcription factor

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Authors: Harika Atmaca, Emir Bozkurt, Latife Merve Oktay, Selim Uzunoglu, Ruchan Uslu, Burçak Karaca

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Microarrays have been developed for highly parallel enzyme-linked immunosorbent assay (ELISA) applications. The most common protein arrays are produced by using multiple monoclonal antibodies, since they are robust molecules which can be easily handled and immobilized by standard procedures without loss of activity. Protein expression profiling with protein array technology allows simultaneous analysis of the protein expression pattern of a large number of proteins. Trabectedin, a tetrahydroisoquinoline alkaloid derived from a Caribbean tunicate, Ecteinascidia turbinata, has been shown to have antitumor effects. Here, we used a novel proteomic approach to explore the mechanism of action of trabectedin in prostate cancer cell line PC-3 by apoptosis antibody microarray. XTT cell proliferation kit and Cell Death Detection Elisa Plus Kit (Roche) was used for measuring cytotoxicity and apoptosis. Human Apoptosis Protein Array (R&D Systems) which consists of 35 apoptosis related proteins was used to assess the omic protein expression pattern. Trabectedin induced cytotoxicity and apoptosis in prostate cancer cells in a time and concentration-dependent manner. The expression levels of the death receptor pathway molecules, TRAIL-R1/DR4, TRAIL R2/DR5, TNF R1/TNFRSF1A, FADD were significantly increased by 4.0-, 21.0-, 4.20- and 11.5-fold by trabectedin treatment in PC-3 cells. Moreover, mitochondrial pathway related pro-apoptotic proteins Bax, Bad, Cytochrome c, and Cleaved Caspase-3 expressions were induced by 2.68-, 2.07-, 2.8-, and 4.5-fold and the expression levels of anti-apoptotic proteins Bcl-2 and Bcl-XL were reduced by 3.5- and 5.2-fold in PC-3 cells. Proteomic (antibody microarray) analysis suggests that the mechanism of action of trabectedin may be exerted via the induction of both intrinsic and extrinsic apoptotic pathways. The antibody microarray platform can be utilised to explore the molecular mechanism of action of novel anticancer agents.

Keywords: trabectedin, prostate cancer, omic protein expression profile, apoptosis

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Authors: Nusrat Praween, Krishna Thej Pammi Guru, Palash Kumar Basu

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Designing non-invasive biosensors for cancer diagnosis is essential for developing an affordable and specific tool to measure cancer-related exosome biomarkers. Exosomes, released by healthy as well as cancer cells, contain valuable information about the biomarkers of various diseases, including cancer. Despite the availability of various isolation techniques, ultracentrifugation is the standard technique that is being employed. Post isolation, exosomes are traditionally exposed to detergents for extracting their proteins, which can often lead to protein degradation. Further to this, it is very essential to develop a sensing platform for the quantification of clinically relevant proteins in a wider range to ensure practicality. In this study, exosomes were immobilized on the Au Screen Printed Electrode (SPE) using EDC/NHS chemistry to facilitate binding. After immobilizing the exosomes on the screen-printed electrode (SPE), we investigated the impact of the electric field by applying various voltages to induce exosome lysis and release their contents. The lysed solution was used for sensing TSG101, a crucial biomarker associated with various cancers, using both faradaic and non-faradaic electrochemical impedance spectroscopy (EIS) methods. The results of non-faradaic and faradaic EIS were comparable and showed good consistency, indicating that non-faradaic sensing can be a reliable alternative. Hence, the non-faradaic sensing technique was used for label-free quantification of the TSG101 biomarker. The results were validated using ELISA. Our electrochemical immunosensor demonstrated a consistent response of TSG101 from 125 pg/mL to 8000 pg/mL, with a detection limit of 0.125 pg/mL at room temperature. Additionally, since non-faradic sensing is label-free, the ease of usage and cost of the final sensor developed can be reduced. The proposed immunosensor is capable of detecting the TSG101 protein at low levels in healthy serum with good sensitivity and specificity, making it a promising platform for biomarker detection.

Keywords: biosensor, exosomes isolation on SPE, electric field lysis of exosome, EIS sensing of TSG101

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