Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 45

Search results for: lymphoma

45 Plasmablastic Lymphoma a New Entity in Patients with HIV Infections

Authors: Rojith K. Balakrishnan

Abstract:

Plasmablastic lymphoma (PBL) is an uncommon, recently described B-cell derived lymphoma that is most commonly seen in patients with Human Immunodeficiency Virus (HIV) infection. Here we report a case of PBL in a 35 year old man with HIV who presented with multiple subcutaneous swellings all over the body and oral mucosal lesions.The biopsy report was suggestive of Diffuse Large B Cell Lymphoma. Immunohistochemistry was done which showed, lymphoma cells, positive for MUM1, CD 138, and VS 38. The proliferation index (MIB) was 95%. Final report was consistent with the diagnosis of Plasmablastic Lymphoma. The lesion completely regressed after treatment with systemic chemotherapy. Up to date, only a few cases of plasmablastic lymphoma have been reported from India. Increased frequency of this lymphoma in HIV patients and rarity of the tumour, along with rapid response of the same to chemotherapy, make this case a unique one. Hence the knowledge about this new entity is important for clinicians who deal with HIV patients.

Keywords: human immunodeficiency virus (HIV), oral cavity lesion, plasmablastic lymphoma, subcutaneous swelling

Procedia PDF Downloads 167
44 The Clinical and Survival Differences between Primary B-cell and T/NK-cell non-Hodgkin lymphomas in the Nasopharynx, Nasal cavity and Nasal sinus: a Population-based Study of 3839 cases in the SEER database

Authors: Jiajia Peng, Danni Cheng, Jianqing Qiu, Yufang Rao, Minzi Mao, Ke Qiu, Junhong Li, Fei Chen, Feng Liu, Jun Liu, Xiaosong Mu, Wenxin Yu, Wei Zhang, Wei Xu, Yu Zhao, Jianjun Ren

Abstract:

Background: Currently, primary B-cell non-Hodgkin lymphoma (B-NHL) and T/NK-cell non-Hodgkin lymphoma (NKT-NHL) originated fromnasal cavity (NC), nasopharynx (NP), and nasal sinus (NS) distinguished unclearly in clinic. Objective: We sought to compare the clinical and survival differences of B-NHL and NKT-NHL occurred in NC, NP, and NS, respectively. Methods: Retrospectivedata of patients diagnosed with nasal cavity lymphoma (NCL), nasopharyngeal lymphoma (NPL), and nasal sinus lymphoma (NSL) between 1975 and 2017 from the Surveillance, Epidemiology, and End Results (SEER) database were collected. We identified the B/NKT-NHL patients based on the histological type and performed univariate, multivariate, and Kaplan-Meier analyses to investigate the survival rates. Results: Of the identified 3,101 B-NHL and 738 NKT-NHL patients, those with B-NHL in NP were the majority (43%) and had better cancer-specific survival than those in NC and NS during2010 to 2017(5-year-CSS, NC vs. NP vs. NS: 81% vs. 83% vs. 82%). In contrast, most of the NKT-NHL originated from NC (68%) and had the highest CSS rate in the recent 7 years (2010-2017, 5-year-CSS: 63%). Additionally, the survival outcomes of patients with NKT-NHL-NP(HR: 1.34, 95% CI: 0.62-2.89, P=0.460)who had received surgery were much worse than those of patients with NKT-NHL-NC (HR: 1.07, 95% CI: 0.75-1.52, P=0.710)and NKT-NHL-NS (HR: 1.11, 95% CI: 0.59-2.07, P=0.740).NKT-NHL-NS patients who had radiation performed (HR: 0.38, 95% CI: 0.19-0.73, P=0.004)shown the highest survival rates while chemotherapy performed (HR: 1.01, 95% CI: 0.43-2.37, P=0.980)presented opposite results. Conclusions: AlthoughB-NHL and NKT-NHL originating from NC, NP, and NS had similar anatomical locations, their clinical characteristics, treatment therapies, and prognoses were different in this study. Our findings may suggest that B-NHL and NKT-NHL in NC, NP, and NS should be treated as different diseases in the clinic.

Keywords: nasopharyngeal lymphoma, nasal cavity lymphoma, nasal sinus lymphoma, B-cell non-hodgkin lymphoma, T/NK-cell non-hodgkin lymphoma

Procedia PDF Downloads 62
43 Incidence of Lymphoma and Gonorrhea Infection: A Retrospective Study

Authors: Diya Kohli, Amalia Ardeljan, Lexi Frankel, Jose Garcia, Lokesh Manjani, Omar Rashid

Abstract:

Gonorrhea is the second most common sexually transmitted disease (STDs) in the United States of America. Gonorrhea affects the urethra, rectum, or throat and the cervix in females. Lymphoma is a cancer of the immune network called the lymphatic system that includes the lymph nodes/glands, spleen, thymus gland, and bone marrow. Lymphoma can affect many organs in the body. When a lymphocyte develops a genetic mutation, it signals other cells into rapid proliferation that causes many mutated lymphocytes. Multiple studies have explored the incidence of cancer in people infected with STDs such as Gonorrhea. For instance, the studies conducted by Wang Y-C and Co., as well as Caini, S and Co. established a direct co-relationship between Gonorrhea infection and incidence of prostate cancer. We hypothesize that Gonorrhea infection also increases the incidence of Lymphoma in patients. This research study aimed to evaluate the correlation between Gonorrhea infection and the incidence of Lymphoma. The data for the research was provided by a Health Insurance Portability and Accountability Act (HIPAA) compliant national database. This database was utilized to evaluate patients infected with Gonorrhea versus the ones who were not infected to establish a correlation with the prevalence of Lymphoma using ICD-10 and ICD-9 codes. Access to the database was granted by the Holy Cross Health, Fort Lauderdale for academic research. Standard statistical methods were applied throughout. Between January 2010 and December 2019, the query was analyzed and resulted in 254 and 808 patients in both the infected and control group, respectively. The two groups were matched by Age Range and CCI score. The incidence of Lymphoma was 0.998% (254 patients out of 25455) in the Gonorrhea group (patients infected with Gonorrhea that was Lymphoma Positive) compared to 3.174% and 808 patients in the control group (Patients negative for Gonorrhea but with Lymphoma). This was statistically significant by a p-value < 2.210-16 with an OR= 0.431 (95% CI 0.381-0.487). The patients were then matched by antibiotic treatment to avoid treatment bias. The incidence of Lymphoma was 1.215% (82 patients out of 6,748) in the Gonorrhea group compared to 2.949% (199 patients out of 6748) in the control group. This was statistically significant by a p-value <5.410-10 with an OR= 0.468 (95% CI 0.367-0.596). The study shows a statistically significant correlation between Gonorrhea and a reduced incidence of Lymphoma. Further evaluation is recommended to assess the potential of Gonorrhea in reducing Lymphoma.

Keywords: gonorrhea, lymphoma, STDs, cancer, ICD

Procedia PDF Downloads 112
42 The Role Previous Cytomegalovirus Infection in Subsequent Lymphoma Develompment

Authors: Amalia Ardeljan, Lexi Frankel, Divesh Manjani, Gabriela Santizo, Maximillian Guerra, Omar Rashid

Abstract:

Introduction: Cytomegalovirus (CMV) infection is a widespread infection affecting between 60-70% of people in industrialized countries. CMV has been previously correlated with a higher incidence of Hodgkin Lymphoma compared to noninfected persons. Research regarding prior CMV infection and subsequent lymphoma development is still controversial. With limited evidence, further research is needed in order to understand the relationship between previous CMV infection and subsequent lymphoma development. This study assessed the effect of CMV infection and the incidence of lymphoma afterward. Methods: A retrospective cohort study (2010-2019) was conducted through a Health Insurance Portability and Accountability Act (HIPAA) compliant national database and conducted using International Classification of Disease (ICD) 9th,10th codes, and Current Procedural Terminology (CPT) codes. These were used to identify lymphoma diagnosis in a previously CMV infected population. Patients were matched for age range and Charlson Comorbidity Index (CCI). A chi-squared test was used to assess statistical significance. Results: A total number of 14,303 patients was obtained in the CMV infected group as well as in the control population (matched by age range and CCI score). Subsequent lymphoma development was seen at a rate of 11.44% (1,637) in the CMV group and 5.74% (822) in the control group, respectively. The difference was statistically significant by p= 2.2x10-16, odds ratio = 2.696 (95% CI 2.483- 2.927). In an attempt to stratify the population by antiviral medication exposure, the outcomes were limited by the decreased number of members exposed to antiviral medication in the control population. Conclusion: This study shows a statistically significant correlation between prior CMV infection and an increased incidence of lymphoma afterward. Further exploration is needed to identify the potential carcinogenic mechanism of CMV and whether the results are attributed to a confounding bias.

Keywords: cytomegalovirus, lymphoma, cancer, microbiology

Procedia PDF Downloads 115
41 Oxidative Antioxidative Status and DNA Damage Profile Induced by Chemotherapy in Algerian Children with Lymphoma

Authors: Assia Galleze, Abdurrahim Kocyigit, Nacira Cherif, Nidel Benhalilou, Nabila Attal, Chafia Touil Boukkoffa, Rachida Raache

Abstract:

Introduction and aims: Chemotherapeutic agents used to inhibit cell division and reduce tumor growth, increase reactive oxygen species levels, which contributes to their genotoxicity [1]. The comet assay is an inexpensive and rapid method to detect the damage at cellular levels and has been used in various cancer populations undergoing chemotherapy [2,3]. The present study aim to assess the oxidative stress and the genotoxicity induced by chemotherapy by the determination of plasma malondialdehyde (MDA) level, protein carbonyl (PC) content, superoxide dismutase (SOD) activity and lymphocyte DNA damage in Algerian children with lymphoma. Materials and Methods: For our study, we selected thirty children with lymphoma treated in university hospital of Beni Messous, Algeria, and fifty unrelated subjects as controls, after obtaining the informed consent in accordance with the Declaration of Helsinki (1964). Plasma levels of MDA, PC and SOD activity were spectrophotometrically measured, while DNA damage was assessed by alkaline comet assay in peripheral blood leukocytes. Results and Discussion: Plasma MDA, PC levels and lymphocyte DNA damage, were found to be significantly higher in lymphoma patients than in controls (p < 0.001). Whereas, SOD activity in lymphoma patients was significantly lower than in healthy controls (p < 0.001). There were significant positive correlations between DNA damage, MDA and PC in patients (r = 0.96, p < 0.001, r = 0.97, p < 0.001, respectively), and negative correlation with SOD (r = 0.87, p < 0.01). Conclusion and Perspective: Our results indicated that, leukocytes DNA damage and oxidative stress were significantly higher in lymphoma patients, suggesting that the direct effect of chemotherapy and the alteration of the redox balance may influence oxidative/antioxidative status.

Keywords: chemotherapy, comet assay, DNA damage, lymphoma

Procedia PDF Downloads 46
40 Lymphomas as Estrogen-Regulated Cancers

Authors: M. S. Hasni, J. Guan, K. Yakimchuk, M. Berglund, B. Sander, G. Enblad, R. M. Amini, S. Okret

Abstract:

Lymphomas are generally not considered as endocrine-related cancers. However, most lymphoid malignancies show gender differences in incidence and show prognosis with males being more affected. Furthermore, some epidemiological data indicate a protective role of estrogens against Non-Hodgkin lymphomas. Recent studies have demonstrated estrogen receptor β (ERβ) to be the major ER expressed in normal and malignant cells of lymphoid origin. We have analyzed the effects of estradiol and selective ERα and ERβ agonists on lymphoma growth in culture and in vivo. Treating lymphoma cells with estradiol or ERα selective agonist had minor or no effect on cell growth while selective ERβ agonist treatment showed an antiproliferative effect. When grafting mice with murine T lymphoma cells, male mice developed larger tumors compared to female mice, a difference that was abolished following ovariectomy, demonstrating estrogen-dependent growth in vivo. When subcutaneously grafting lymphoma cells to mice, so far growth of all tested human B lymphoma tumors (Raji and Ramos Burkitt lymphoma, SU.DHL4 (GC) and U2932 (ABC) DLBCL, Granta-519, Maver1 and Z138 MCL cells), were reduced following treatment with ERβ selective agonist (ref. 2 and unpublished). Moreover, the number and size of liver foci of disseminating Raji cells was reduced. We have identified target genes and mechanism that could explain the above effects of ERβ agonists. This included effects on angio and lymphangiogenesis. Now we have further analyzed effects of ERβ agonists on Ibrutinib-sensitive and -insensitive MCL cells in xenograft experiments as well as ERβ expression in primary lymphoma material (DLBCL). Preliminary statistical analysis has been done correlating ERβ expression to other biomarkers and clinical data.

Keywords: lymphomas, estrogen receptors, cancer, liver foci

Procedia PDF Downloads 315
39 Granulomatous Mycoses Fungoides: A Case Report

Authors: Girum Tedla Assefa

Abstract:

Background: Granulomatous mycosis fungoides is an extremely rare type of cutaneous T-cell lymphoma (<55 cases reported worldwide). Case report: A 36-year-old female presented with soft tissue atrophy of right lower limb (dermis + hypodermis) of 22 years and plaques over trunk of 3 years duration. Histological examination of a biopsy taken from the atrophied tissue showed a granulomatous reaction with epidermotropic atypical lymphocytes. However, in other areas there were only findings of conventional MF without granuloma. Conclusion: The diagnosis of a granulomatous mycosis fungoides depends exclusively on the histological demonstration of granulomas. Distinct clinical characteristics are not present. This case highlights the importance of thorough investigation of lipoatrophic skin changes in the adult to exclude underlying causes, including MF.

Keywords: cutaneous lymphoma, granulomatous skin lymphoma, mycoses fungoides, skin atrophy

Procedia PDF Downloads 295
38 Principle Component Analysis on Colon Cancer Detection

Authors: N. K. Caecar Pratiwi, Yunendah Nur Fuadah, Rita Magdalena, R. D. Atmaja, Sofia Saidah, Ocky Tiaramukti

Abstract:

Colon cancer or colorectal cancer is a type of cancer that attacks the last part of the human digestive system. Lymphoma and carcinoma are types of cancer that attack human’s colon. Colon cancer causes deaths about half a million people every year. In Indonesia, colon cancer is the third largest cancer case for women and second in men. Unhealthy lifestyles such as minimum consumption of fiber, rarely exercising and lack of awareness for early detection are factors that cause high cases of colon cancer. The aim of this project is to produce a system that can detect and classify images into type of colon cancer lymphoma, carcinoma, or normal. The designed system used 198 data colon cancer tissue pathology, consist of 66 images for Lymphoma cancer, 66 images for carcinoma cancer and 66 for normal / healthy colon condition. This system will classify colon cancer starting from image preprocessing, feature extraction using Principal Component Analysis (PCA) and classification using K-Nearest Neighbor (K-NN) method. Several stages in preprocessing are resize, convert RGB image to grayscale, edge detection and last, histogram equalization. Tests will be done by trying some K-NN input parameter setting. The result of this project is an image processing system that can detect and classify the type of colon cancer with high accuracy and low computation time.

Keywords: carcinoma, colorectal cancer, k-nearest neighbor, lymphoma, principle component analysis

Procedia PDF Downloads 87
37 Physiological Normoxia and Cellular Adhesion of Diffuse Large B-Cell Lymphoma Primary Cells: Real-Time PCR and Immunohistochemistry Study

Authors: Kamila Duś-Szachniewicz, Kinga M. Walaszek, Paweł Skiba, Paweł Kołodziej, Piotr Ziółkowski

Abstract:

Cell adhesion is of fundamental importance in the cell communication, signaling, and motility, and its dysfunction occurs prevalently during cancer progression. The knowledge of the molecular and cellular processes involved in abnormalities in cancer cells adhesion has greatly increased, and it has been focused mainly on cellular adhesion molecules (CAMs) and tumor microenvironment. Unfortunately, most of the data regarding CAMs expression relates to study on cells maintained in standard oxygen condition of 21%, while the emerging evidence suggests that culturing cells in ambient air is far from physiological. In fact, oxygen in human tissues ranges from 1 to 11%. The aim of this study was to compare the effects of physiological lymph node normoxia (5% O2), and hyperoxia (21% O2) on the expression of cellular adhesion molecules of primary diffuse large B-cell lymphoma cells (DLBCL) isolated from 10 lymphoma patients. Quantitative RT-PCR and immunohistochemistry were used to confirm the differential expression of several CAMs, including ICAM, CD83, CD81, CD44, depending on the level of oxygen. Our findings also suggest that DLBCL cells maintained at ambient O2 (21%) exhibit reduced growth rate and migration ability compared to the cells growing in normoxia conditions. Taking into account all the observations, we emphasize the need to identify the optimal human cell culture conditions mimicking the physiological aspects of tumor growth and differentiation.

Keywords: adhesion molecules, diffuse large B-cell lymphoma, physiological normoxia, quantitative RT-PCR

Procedia PDF Downloads 200
36 Finding Bicluster on Gene Expression Data of Lymphoma Based on Singular Value Decomposition and Hierarchical Clustering

Authors: Alhadi Bustaman, Soeganda Formalidin, Titin Siswantining

Abstract:

DNA microarray technology is used to analyze thousand gene expression data simultaneously and a very important task for drug development and test, function annotation, and cancer diagnosis. Various clustering methods have been used for analyzing gene expression data. However, when analyzing very large and heterogeneous collections of gene expression data, conventional clustering methods often cannot produce a satisfactory solution. Biclustering algorithm has been used as an alternative approach to identifying structures from gene expression data. In this paper, we introduce a transform technique based on singular value decomposition to identify normalized matrix of gene expression data followed by Mixed-Clustering algorithm and the Lift algorithm, inspired in the node-deletion and node-addition phases proposed by Cheng and Church based on Agglomerative Hierarchical Clustering (AHC). Experimental study on standard datasets demonstrated the effectiveness of the algorithm in gene expression data.

Keywords: agglomerative hierarchical clustering (AHC), biclustering, gene expression data, lymphoma, singular value decomposition (SVD)

Procedia PDF Downloads 183
35 Risk of Mortality and Spectrum of Second Primary Malignancies in Mantle Cell Lymphoma before and after Ibrutinib Approval: A Population-Based Study

Authors: Karthik Chamari, Vasudha Rudraraju, Gaurav Chaudhari

Abstract:

Background: Mantle cell lymphoma (MCL) is one of the mature B cell non-Hodgkin lymphomas (NHL). The course of MCL is moderately aggressive and variable, and it has median overall survival of 8 to 10 years. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, was approved by the United States (US) Food and Drug Administration in November of 2013 for the treatment of MCL patients who have received at least one prior therapy. In this study, we aimed to evaluate whether there has been a change in survival and patterns of second primary malignancies (SPMs) among the MCL population in the US after ibrutinib approval. Methods: Using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER)-18, we conducted a retrospective study with patients diagnosed with MCL (ICD-0-3 code 9673/3) between 2007 and 2018. We divided patients into two six-year cohorts, pre-ibrutinib approval (2007-2012) and post-ibrutinib approval (2013-2018), and compared relative survival rates (RSRs) and standardized incidence ratios (SIRs) of SPMs between cohorts. Results: We included 9,257 patients diagnosed with MCL between 2007 and 2018 in the SEER-18 survival and SIR registries. Of these, 4,205 (45%) patients were included in the pre-ibrutinib cohort, and 5052 (55%) patients were included in the post-ibrutinib cohort. The median follow-up duration for the pre-ibrutinib cohort was 54 months (range 0 to 143 months), and the post-ibrutinib cohort was 20 months (range 0 to 71 months). There was a significant difference in the five-year RSRs between pre-ibrutinib and post-ibrutinib cohorts (57.5% vs. 62.6%, p < 0.005). Out of the 9,257 patients diagnosed with MCL, 920 developed SPMs. A higher proportion of SPMs occurred in the post-ibrutinib cohort (63%) when compared with the pre-ibrutinib cohort (37%). Non-hematological malignancies comprised most of all SPMs. A higher incidence of non-hematological malignancies occurred in the post-ibrutinib cohort (SIR 1.42, 95% CI 1.29 to 1.56) when compared with the pre-ibrutinib cohort (SIR 1.14, 95% CI 1 to 1.3). There was a statistically significant increase in the incidence of cancers of the respiratory tract (SIR 1.77, 95% CI 1.43 to 2.18), urinary tract (SIR 1.61, 95% CI 1.23 to 2.06) when compared with other non-hematological malignancies in post-ibrutinib cohort. Conclusions: Our study results suggest the relative survival rates have increased since the approval of ibrutinib for mantle cell lymphoma patients. Additionally, for some unclear reasons, the incidence of SPM’s (non-hematological malignancies), mainly cancers of the respiratory tract, urinary tract, have increased in the six years following the approval of ibrutinib. Further studies should be conducted to determine the cause of these findings.

Keywords: mantle cell lymphoma, Ibrutinib, relative survival analysis, secondary primary cancers

Procedia PDF Downloads 97
34 Differential Infection of Primary Human B-Cells and EBV Positive B-Lymphoma Cell Lines by Recombinant AAV Serotypes

Authors: Elham Ahmadi, Mehrdad Ravanshad, Joyce Fingeroth, Mazyar Ziyaeyan, Rajesh Panigrahi, Jun Xie, Gao Guangping

Abstract:

B-cell proliferative disorders often occur among persons that are T-cell compromised. These disorders are primarily EBV+ and can first present with a focal lesion. Direct introduction of oncolytic viruses into localized tumors provides theoretical advantages over chemotherapy and immunotherapy by reducing systemic toxicity, to which the immunocompromised host is most vulnerable. Widely studied as a vehicle for gene therapy, AAV has only rarely been applied to treat cancer. As a prelude to development of a therapeutic vehicle, we assessed the ability of 15 distinct recombinant AAV serotypes (rAAV1, rAAV2, rAAV3b, rAAV4, rAAV5, rAAV6, rAAV6.2, rAAV6TM, rAAV7, rAAV8, rAAVrh8, rAAV9, rAAVrh10, rAAV39, rAAV43) bearing eGFP to infect human B-cell tumor lines compared with primary B-cells in vitro. Enhanced infection of tumor lines by AAV 6.2 was demonstrated by flow cytometry. EBV superinfection of EBV negative B-cell tumor lines increased susceptibility to AAV6.2 infection. As proof of concept, AAV6.2 bearing HSV-1 thymidine kinase in place of eGFP eliminated tumor cells upon exposure to ganciclovir.

Keywords: AAV, gene therapy, lymphoma, malignancy, tropism

Procedia PDF Downloads 40
33 Diagnostic Accuracy Of Core Biopsy In Patients Presenting With Axillary Lymphadenopathy And Suspected Non-Breast Malignancy

Authors: Monisha Edirisooriya, Wilma Jack, Dominique Twelves, Jennifer Royds, Fiona Scott, Nicola Mason, Arran Turnbull, J. Michael Dixon

Abstract:

Introduction: Excision biopsy has been the investigation of choice for patients presenting with pathological axillary lymphadenopathy without a breast abnormality. Core biopsy of nodes can provide sufficient tissue for diagnosis and has advantages in terms of morbidity and speed of diagnosis. This study evaluates the diagnostic accuracy of core biopsy in patients presenting with axillary lymphadenopathy. Methods: Between 2009 and 2019, 165 patients referred to the Edinburgh Breast Unit had a total of 179 axillary lymph node core biopsies. Results: 152 (92%) of the 165 initial core biopsies were deemed to contain adequate nodal tissue. Core biopsy correctly established malignancy in 75 of the 78 patients with haematological malignancy (96%) and in all 28 patients with metastatic carcinoma (100%) and correctly diagnosed benign changes in 49 of 57 (86%) patients with benign conditions. There were no false positives and no false negatives. In 67 (85.9%) of the 78 patients with hematological malignancy, there was sufficient material in the first core biopsy to allow the pathologist to make an actionable diagnosis and not ask for more tissue sampling prior to treatment. There were no complications of core biopsy. On follow up, none of the patients with benign cores has been shown to have malignancy in the axilla and none with lymphoma had their initial disease incorrectly classified. Conclusions: This study shows that core biopsy is now the investigation of choice for patients presenting with axillary lymphadenopathy even in those suspected as having lymphoma.

Keywords: core biopsy, excision biopsy, axillary lymphadenopathy, non-breast malignancy

Procedia PDF Downloads 127
32 Giant Cancer Cell Formation: A Link between Cell Survival and Morphological Changes in Cancer Cells

Authors: Rostyslav Horbay, Nick Korolis, Vahid Anvari, Rostyslav Stoika

Abstract:

Introduction: Giant cancer cells (GCC) are common in all types of cancer, especially after poor therapy. Some specific features of such cells include ~10-fold enlargement, drug resistance, and the ability to propagate similar daughter cells. We used murine NK/Ly lymphoma, an aggressive and fast growing lymphoma model that has already shown drastic changes in GCC comparing to parental cells (chromatin condensation, nuclear fragmentation, tighter OXPHOS/cellular respiration coupling, multidrug resistance). Materials and methods: In this study, we compared morpho-functional changes of GCC that predominantly show either a cytostatic or a cytotoxic effect after treatment with drugs. We studied the effect of a combined cytostatic/cytotoxic drug treatment to determine the correlation of drug efficiency and GCC formation. Doses of G1/S-specific drug paclitaxel/PTX (G2/M-specific, 50 mg/mouse), vinblastine/VBL (50 mg/mouse), and DNA-targeting agents doxorubicin/DOX (125 ng/mouse) and cisplatin/CP (225 ng/mouse) on C57 black mice. Several tests were chosen to estimate morphological and physiological state (propidium iodide, Rhodamine-123, DAPI, JC-1, Janus Green, Giemsa staining and other), which included cell integrity, nuclear fragmentation and chromatin condensation, mitochondrial activity, and others. A single and double factor ANOVA analysis were performed to determine correlation between the criteria of applied drugs and cytomorphological changes. Results: In all cases of treatment, several morphological changes were observed (intracellular vacuolization, membrane blebbing, and interconnected mitochondrial network). A lower gain in ascites (49.97% comparing to control group) and longest lifespan (22+9 days) after tumor injection was obtained with single VBL and single DOX injections. Such ascites contained the highest number of GCC (83.7%+9.2%), lowest cell count number (72.7+31.0 mln/ml), and a strong correlation coefficient between increased mitochondrial activity and percentage of giant NK/Ly cells. A high number of viable GCC (82.1+9.2%) was observed compared to the parental forms (15.4+11.9%) indicating that GCC are more drug resistant than the parental cells. All this indicates that the giant cell formation and its ability to obtain drug resistance is an expanding field in cancer research.

Keywords: ANOVA, cisplatin, doxorubicin, drug resistance, giant cancer cells, NK/Ly lymphoma, paclitaxel, vinblastine

Procedia PDF Downloads 132
31 Assessment of Isatin as Surface Recognition Group: Design, Synthesis and Anticancer Evaluation of Hydroxamates as Novel Histone Deacetylase Inhibitors

Authors: Harish Rajak, Kamlesh Raghuwanshi

Abstract:

Histone deacetylase (HDAC) are promising target for cancer treatment. The panobinostat (Farydak; Novartis; approved by USFDA in 2015) and chidamide (Epidaza; Chipscreen Biosciences; approved by China FDA in 2014) are the novel HDAC inhibitors ratified for the treatment of patients with multiple myeloma and peripheral T cell lymphoma, respectively. On the other hand, two other HDAC inhibitors, Vorinostat (SAHA; approved by USFDA in 2006) and Romidepsin (FK228; approved by USFDA in 2009) are already in market for the treatment of cutaneous T-cell lymphoma. Several hydroxamic acid based HDAC inhibitors i.e., belinostat, givinostat, PCI24781 and JNJ26481585 are in clinical trials. HDAC inhibitors consist of three pharmacophoric features - an aromatic cap group, zinc binding group (ZBG) and a linker chain connecting cap group to ZBG. Herein, we report synthesis, characterization and biological evaluation of HDAC inhibitors possessing substituted isatin moiety as cap group which recognize the surface of active enzyme pocket and thiosemicarbazide moiety incorporated as linker group responsible for connecting cap group to ZBG (hydroxamic acid). Several analogues were found to inhibit HDAC and cellular proliferation of Hela cervical cancer cells with GI50 values in the micro molar range. Some of the compounds exhibited promising results in vitro antiproliferative studies. Attempts were also made to establish the structure activity relationship among synthesized HDAC inhibitors.

Keywords: HDAC inhibitors, hydroxamic acid derivatives, isatin derivatives, antiproliferative activity, docking

Procedia PDF Downloads 218
30 Comparison with Two Clinical Cases of Plasma Cell Neoplasm by Using the Method of Capillary Electrophoresis

Authors: Kai Pai Huang

Abstract:

Background: There are several types of plasma cell neoplasms including multiple myeloma, plasmacytoma, lymphoplasmacytic lymphoma, and monoclonal gammopathy of undetermined significance (MGUS) are found in our lab. Today, we want to compare with two cases using the method of capillary electrophoresis. Method: Serum is prepared and electrophoresis is performed at alkaline PH in a capillary using the Sebia® Capillary 2. Albumin and globulins are detected by the detector which is located in the cathode of the capillary and the signals are transformed to peaks. Serum was treated with beta-mercaptoethanol which reducing the polymerized immunoglobulin to monomer immunoglobulin to clarify two M-protein are secreted from the same plasma cell clone in bone marrow. Result: Case 1: A 78-year-old female presenting dysuria, oliguria and leg edema for several months. Laboratory data showed proteinuria, leukocytosis, results of high serum IgA and lambda light chain. A renal biopsy found amyloid fibrils in the glomerular mesangial area. Serum protein electrophoresis shows a major monoclonal peak in the β region and minor small peak in gamma region, and the immunotyping studies for serum showed two IgA/λ type. Case 2: A 55-year-old male presenting abdominal distension and low back pain for more than one month. Laboratory data showed T12 T8 compression fracture, results of high serum IgM and kappa light chain. Bone marrow aspiration showed the cells from the bone marrow are B cells with monotypic kappa chain expression. Bone marrow biopsy found this is lymphoplasmacytic lymphoma (Waldenstrom macroglobulin). Serum protein electrophoresis shows a monoclonal peak in the β region and the immunotyping studies for serum showed IgM/κ type. Conclusion: Plasma cell neoplasm can be diagnosed by many examinations. Among them, using capillary electrophoresis by a lab can separate several types of gammopathy and the quantification of a monoclonal peak can be used to evaluate the patients’ prognosis or treatment.

Keywords: plasma cell neoplasm, capillary electrophoresis, serum protein electrophoresis, immunotyping

Procedia PDF Downloads 65
29 Spontaneous Tumour Lysis in Acute Myeloid Leukemia

Authors: Rojith K. Balakrishnan

Abstract:

Spontaneous tumour lysis syndrome is a constellation of electrolyte abnormalities and an acute renal failure which occurs in the setting of rapid cell turnover prior to the administration of cytotoxic chemotherapy. While spontaneous tumour lysis well-described in patients with Burkitt lymphoma, it is thought to occur less commonly in patients with other hematological malignancies. We present a case of forty-year-old female who presented with features of acute renal failure, on further evaluation turned out to be a newly diagnosed acute myeloid leukemia with spontaneous tumour lysis best of our knowledge only three cases of AML with spontaneous tumour lysis has reported world wide.

Keywords: AML, tumour lysis, renal failure, myeloid leukemia

Procedia PDF Downloads 202
28 Minimizing the Impact of Covariate Detection Limit in Logistic Regression

Authors: Shahadut Hossain, Jacek Wesolowski, Zahirul Hoque

Abstract:

In many epidemiological and environmental studies covariate measurements are subject to the detection limit. In most applications, covariate measurements are usually truncated from below which is known as left-truncation. Because the measuring device, which we use to measure the covariate, fails to detect values falling below the certain threshold. In regression analyses, it causes inflated bias and inaccurate mean squared error (MSE) to the estimators. This paper suggests a response-based regression calibration method to correct the deleterious impact introduced by the covariate detection limit in the estimators of the parameters of simple logistic regression model. Compared to the maximum likelihood method, the proposed method is computationally simpler, and hence easier to implement. It is robust to the violation of distributional assumption about the covariate of interest. In producing correct inference, the performance of the proposed method compared to the other competing methods has been investigated through extensive simulations. A real-life application of the method is also shown using data from a population-based case-control study of non-Hodgkin lymphoma.

Keywords: environmental exposure, detection limit, left truncation, bias, ad-hoc substitution

Procedia PDF Downloads 162
27 Protective Effect of the Standardized Extract of Holmskioldia sanguinea on Tumor Bearing Mice

Authors: Mahesh Pal, Tripti Mishra, Chandana Rao, Dalip Upreti

Abstract:

Cancer has been considered to be a very dreadful disease. Holmskioldia sanguinea is a large climbing shrub found in the Himalayas at an altitude of 5,000 ft and preliminary investigation showed the excellent yield of andrographolide and subjected for the anticancer activity. Protective effect of Holmskioldia sanguinea leaf ethanolic extract has been investigated against Ehrlich ascites carcinoma (EAC) and Daltons ascites lymphoma (DAL) in Swiss albino mice to evaluate the possible mechanism of action. The enzymatic antioxidant status was studied on tumor bearing mice, which shows the potential of the compound to possess significant free radical scavenging property and revealed significant tumor regression and prolonged survival time. The isolated bioactive molecule andrographolide from Holmskioldia sanguinea yields (2.5%) in subject to HPTLC/HPLC analysis. The cellular defense system constituting the superoxide dismutase, catalyses was enhanced whereby the lipid peroxidation content was restricted to a larger extent. The Holmskioldia sanguinea is a new source of andrographolide and demonstrated the potency in treatment of cancer.

Keywords: Holmskioldia sanguinea, tumor, mice, andrographolide

Procedia PDF Downloads 170
26 Bcl-2: A Molecule to Detect Oral Cancer and Precancer

Authors: Vandana Singh, Subash Singh

Abstract:

Introduction: Oral squamous cell carcinoma is the most common malignant tumor of the oral cavity. Normally the death of cell and the growth are active processes and depend not only on external factors but also on the expression of genes like Bcl-2, which activate and inhibit apoptosis. The term Bcl-2 is an acronym for B-cell lymphoma/ leukemia -2 genes. Objectives: An attempt was made to evaluate Bcl-2 oncoprotein expression in patients with oral precancer and cancer and to assess possible correlation between Bcl-2 oncoprotein expression and clinicopathological features of oral precancer and cancer. Material and Methods: This is a selective prospective clinical and immunohistochemical study. Clinicopathological examination is correlated with immunohistochemical findings. The immunolocalization of Bcl-2 protein is performed using the labeled streptavidin biotin (LSAB) method. To visualize the reaction, 3, 3-diaminobenzidine (DAB) is used. Results: Bcl-2 expression was positive in 11 [36.66 %, low Bcl-2 expression 3 (10.00 %), moderate Bcl-2 expression 7 (23.33 %), and high Bcl-2 expression 1 (3.33 %)] oral cancer cases and in 14 [87.50 %, low expression 8 (50 %), moderate expression 6 (37.50 %)] precancer cases. Conclusion: On the basis of the results of our study we conclude that positive Bcl-2 expression may be an indicator of poor prognosis in oral cancer and precancer. Relevance: It has been reported that there is deregulation of Bcl-2 expression during progression from oral epithelial dysplasia to squamous cell carcinoma. It can be used for revealing progression of epithelial dysplasia to malignancy and as a prognostic marker in oral precancer and cancer.

Keywords: BcL-2, immunohistochemistry, oral cancer, oral precancer

Procedia PDF Downloads 182
25 Meningeal Hemangiopericytoma in an HIV-Positive Patient: A Case Report and Review of Literature

Authors: Roland Benedict Reyes, Marc Edsel Ayes, Regina Berba, Cybele Lara Abad

Abstract:

Background: Three AIDS-defining malignancies have been associated with the human immunodeficiency virus (HIV): Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and cervical carcinoma. However, new cases of non-AIDS defining malignancies also have been increasingly associated with HIV. One of these is a rare intracranial malignancy, meningeal hemangiopericyotma. Case Description: A 32-year old HIV-positive male, not on highly active antiretroviral therapy, was admitted to our hospital due to generalized weakness and sudden onset hearing loss. Cranial MRI was done, which revealed a temporal nodule with the following considerations: granuloma, meningioma or metastases. A craniotomy was performed and the mass excised. Results from the biopsy showed meningeal hemangiopericytoma. The patient was then started on antiretroviral therapy (Lamivudine, Tenofovir, and Efavirenz) and was discharged for radiation therapy and metastatic work-up as an outpatient. On follow-up seven months later, metastatic work up revealed multiple hepatic foci not previously documented suggestive of metastasis short of biopsy sampling. Conclusions: This case of an intracranial hemangiopericytoma in an HIV-positive patient is the second case thus far presented, based on our systematic and extensive search of the literature.

Keywords: Hemangiopericytoma, Human Immunodeficiency Virus, Meningeal hemangiopericytoma, Neoplasm

Procedia PDF Downloads 378
24 Epidemiological-Anatomopathological-Immunohistochemical Profile of Gastric Cancer throughout Eastern Algeria

Authors: S. Tebibel, R. L. Bouchouka, C. Mechati, S. Messaoudi

Abstract:

The stomach cancer or gastric cancer is an aggressive cancer with a significant geographic disparity. The decrease in frequency is attributed to refrigeration, which has several beneficial consequences, increased consumption of fresh fruits and vegetables, reduced consumption of salt, which was widely used as a food preservative, and less contamination of food by carcinogenic compounds. The infection with Helicobacter pylori is responsible for progressive inflammatory changes in the gastric mucosa usually evolving into stomach cancer in 80% of cases. Methodology: This epidemiological and analytical study concerns 65 patients (46 men and 19 women) with gastric adenocarcinomas with an average age of 56.5 years and a male predominance with a sex ratio of 2.4. Results and Discussion: In this series, the clinical symptoms are dominated by epigastralgia (72.31%), vomiting (27,69%), and slimming (24,62%). The FOGD (Oeso-Gastro Duodenal Fibroscopy) performed in the 65 patients revealed a predominance of the antro-pyloric localization in 19 cases (i.e., 29.23%) and anulcerative budding appearance in 33 subjects (50,77%). Histologically, the moderately differentiated adenocarcinoma is found in 30.77% of patients, followed by well differentiated adenocarcinoma with 26.15% of patients. The immunohistochemical study revealed a positive labeling of half of the T cells by anti-CD3 AC, and a positive labeling of anti-CD20 AC in a diffuse and intense manner, with the presence of CD20-positive lymphoepithelial lesions compatible with CD20 a low grade MALT non-Hodgkin's lymphoma. Conclusion: This framework of analysis revealed some risk factors for gastric cancer, such as food, hygiene, Helicobacter pylori infection, smoking and family history.

Keywords: cancer, Helicobacter pylori, immunohistochemistry, stomach

Procedia PDF Downloads 58
23 Role of Imaging in Predicting the Receptor Positivity Status in Lung Adenocarcinoma: A Chapter in Radiogenomics

Authors: Sonal Sethi, Mukesh Yadav, Abhimanyu Gupta

Abstract:

The upcoming field of radiogenomics has the potential to upgrade the role of imaging in lung cancer management by noninvasive characterization of tumor histology and genetic microenvironment. Receptor positivity like epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genotyping are critical in lung adenocarcinoma for treatment. As conventional identification of receptor positivity is an invasive procedure, we analyzed the features on non-invasive computed tomography (CT), which predicts the receptor positivity in lung adenocarcinoma. Retrospectively, we did a comprehensive study from 77 proven lung adenocarcinoma patients with CT images, EGFR and ALK receptor genotyping, and clinical information. Total 22/77 patients were receptor-positive (15 had only EGFR mutation, 6 had ALK mutation, and 1 had both EGFR and ALK mutation). Various morphological characteristics and metastatic distribution on CT were analyzed along with the clinical information. Univariate and multivariable logistic regression analyses were used. On multivariable logistic regression analysis, we found spiculated margin, lymphangitic spread, air bronchogram, pleural effusion, and distant metastasis had a significant predictive value for receptor mutation status. On univariate analysis, air bronchogram and pleural effusion had significant individual predictive value. Conclusions: Receptor positive lung cancer has characteristic imaging features compared with nonreceptor positive lung adenocarcinoma. Since CT is routinely used in lung cancer diagnosis, we can predict the receptor positivity by a noninvasive technique and would follow a more aggressive algorithm for evaluation of distant metastases as well as for the treatment.

Keywords: lung cancer, multidisciplinary cancer care, oncologic imaging, radiobiology

Procedia PDF Downloads 37
22 Microbiota Effect with Cytokine in Hl and NHL Patient Group

Authors: Ekin Ece Gürer, Tarık Onur Tiryaki, Sevgi Kalayoğlu Beşışık, Fatma Savran Oğuz, Uğur Sezerman, Fatma Erdem, Gülşen Günel, Dürdane Serap Kuruca, Zerrin Aktaş, Oral Öncül

Abstract:

Aim: Chemotherapytreatment in HodgkinLymphomaandNon-HodgkinLymphoma (NHL) diseasescausesgastrointestinalepithelialdamage, disruptstheintestinalmicrobiotabalanceandcausesdysbiosis. Inourstudy, it wasaimedtoshowtheeffect of thedamagecausedbychemotherapy on themicrobiotaandtheeffect of thechangingmicrobiota flora on thecourse of thedisease. Materials And Methods: Seven adult HL and seven adult HL patients to be treatedwithchemotherapywereincluded in the study. Stoolsamplesweretakentwice, beforechemotherapytreatmentandafterthe 3th course of treatment. SamplesweresequencedusingNextGenerationSequencing (NGS) methodafternucleicacidisolation. OTU tableswerepreparedusing NCBI blastnversion 2.0.12 accordingtothe NCBI general 16S bacterialtaxonomyreferencedated 10.08.2021. Thegenerated OTU tableswerecalculatedwith R Statistical Computer Language version 4.04 (readr, phyloseq, microbiome, vegan, descrand ggplot2 packages) to calculate Alpha diversityandtheirgraphicswerecreated. Statistical analyzeswerealsoperformedusing R Statistical Computer Language version 4.0.4 and studio IDE 1.4 (tidyverse, readr, xlsxand ggplot2 packages). Expression of IL-12 and IL-17 cytokineswasperformedbyrtPCRtwice, beforeandaftertreatment. Results: InHL patients, a significantdecreasewasobserved in themicrobiota flora of Ruminococcaceae_UCG-014 genus (p:0.036) andUndefined Ruminococcaceae_UCG-014 species (p:0.036) comparedtopre-treatment. When the post-treatment of HL patientswerecomparedwithhealthycontrols, a significantdecreasewasfound in themicrobiota of Prevotella_7 genus (p:0.049) andButyricimonas (p:0.006) in the post-treatmentmicrobiota of HL patients. InNHL patients, a significantdecreasewasobserved in themicrobiota flora of Coprococccus_3 genus (p:0.015) andUndefined Ruminoclostridium_5 (p:0.046) speciescomparedtopre-treatment. When post-treatment of NHL patientswerecomparedwithhealthycontrols, a significantabundance in theBacilliclass (p:0.029) and a significantdecrease in theUndefinedAlistipesspecies (p:0.047) wereobserved in the post-treatmentmicrobiota of NHL patients. While a decreasewasobserved in IL-12 cytokineexpressionuntilbeforetreatment, an increase in IL-17 cytokineexpressionwasdetected. Discussion: Intestinal flora monitoringafterchemotherapytreatmentshowsthat it can be a guide in thetreatment of thedisease. It is thoughtthatincreasingthediversity of commensalbacteria can alsopositivelyaffecttheprognosis of thedisease.

Keywords: hodgkin lymphoma, non-hodgkin, microbiota, cytokines

Procedia PDF Downloads 4
21 An Unbiased Profiling of Immune Repertoire via Sequencing and Analyzing T-Cell Receptor Genes

Authors: Yi-Lin Chen, Sheng-Jou Hung, Tsunglin Liu

Abstract:

Adaptive immune system recognizes a wide range of antigens via expressing a large number of structurally distinct T cell and B cell receptor genes. The distinct receptor genes arise from complex rearrangements called V(D)J recombination, and constitute the immune repertoire. A common method of profiling immune repertoire is via amplifying recombined receptor genes using multiple primers and high-throughput sequencing. This multiplex-PCR approach is efficient; however, the resulting repertoire can be distorted because of primer bias. To eliminate primer bias, 5’ RACE is an alternative amplification approach. However, the application of RACE approach is limited by its low efficiency (i.e., the majority of data are non-regular receptor sequences, e.g., containing intronic segments) and lack of the convenient tool for analysis. We propose a computational tool that can correctly identify non-regular receptor sequences in RACE data via aligning receptor sequences against the whole gene instead of only the exon regions as done in all other tools. Using our tool, the remaining regular data allow for an accurate profiling of immune repertoire. In addition, a RACE approach is improved to yield a higher fraction of regular T-cell receptor sequences. Finally, we quantify the degree of primer bias of a multiplex-PCR approach via comparing it to the RACE approach. The results reveal significant differences in frequency of VJ combination by the two approaches. Together, we provide a new experimental and computation pipeline for an unbiased profiling of immune repertoire. As immune repertoire profiling has many applications, e.g., tracing bacterial and viral infection, detection of T cell lymphoma and minimal residual disease, monitoring cancer immunotherapy, etc., our work should benefit scientists who are interested in the applications.

Keywords: immune repertoire, T-cell receptor, 5' RACE, high-throughput sequencing, sequence alignment

Procedia PDF Downloads 94
20 Comparative in silico and in vitro Study of N-(1-Methyl-2-Oxo-2-N-Methyl Anilino-Ethyl) Benzene Sulfonamide and Its Analogues as an Anticancer Agent

Authors: Pamita Awasthi, Kirna, Shilpa Dogra, Manu Vatsal, Ritu Barthwal

Abstract:

Doxorubicin, also known as adriamycin, is an anthracycline class of drug used in cancer chemotherapy. It is used in the treatment of non-Hodgkin’s lymphoma, multiple myeloma, acute leukemias, breast cancer, lung cancer, endometrium cancer and ovary cancers. It functions via intercalating DNA and ultimately killing cancer cells. The major side effects of doxorubicin are hair loss, myelosuppression, nausea & vomiting, oesophagitis, diarrhoea, heart damage and liver dysfunction. The minor modifications in the structure of compound exhibit large variation in the biological activity, has prompted us to carry out the synthesis of sulfonamide derivatives. Sulfonamide is an important feature with broad spectrum of biological activity such as antiviral, antifungal, diuretics, anti-inflammatory, antibacterial and anticancer activities. Structure of the synthesized compound N-(1-methyl-2-oxo-2-N-methyl anilino-ethyl)benzene sulfonamide confirmed by proton nuclear magnetic resonance (1H NMR),13C NMR, Mass and FTIR spectroscopic tools to assure the position of all protons and hence stereochemistry of the molecule. Further we have reported the binding potential of synthesized sulfonamide analogues in comparison to doxorubicin drug using Auto Dock 4.2 software. Computational binding energy (B.E.) and inhibitory constant (Ki) has been evaluated for the synthesized compound in comparison of doxorubicin against Poly (dA-dT).Poly (dA-dT) and Poly (dG-dC).Poly (dG-dC) sequences. The in vitro cytotoxic study against human breast cancer cell lines confirms the better anticancer activity of the synthesized compound over currently in use anticancer drug doxorubicin. The IC50 value of the synthesized compound is 7.12 µM where as for doxorubicin is 7.2 µ.

Keywords: Doxorubicin, auto dock, in silco, in vitro

Procedia PDF Downloads 334
19 Beta-Carotene Attenuates Cognitive and Hepatic Impairment in Thioacetamide-Induced Rat Model of Hepatic Encephalopathy via Mitigation of MAPK/NF-κB Signaling Pathway

Authors: Marawan Abd Elbaset Mohamed, Hanan A. Ogaly, Rehab F. Abdel-Rahman, Ahmed-Farid O.A., Marwa S. Khattab, Reham M. Abd-Elsalam

Abstract:

Liver fibrosis is a severe worldwide health concern due to various chronic liver disorders. Hepatic encephalopathy (HE) is one of its most common complications affecting liver and brain cognitive function. Beta-Carotene (B-Car) is an organic, strongly colored red-orange pigment abundant in fungi, plants, and fruits. The study attempted to know B-Car neuroprotective potential against thioacetamide (TAA)-induced neurotoxicity and cognitive decline in HE in rats. Hepatic encephalopathy was induced by TAA (100 mg/kg, i.p.) three times per week for two weeks. B-Car was given orally (10 or 20 mg/kg) daily for two weeks after TAA injections. Organ body weight ratio, Serum transaminase activities, liver’s antioxidant parameters, ammonia, and liver histopathology were assessed. Also, the brain’s mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB), antioxidant parameters, adenosine triphosphate (ATP), adenosine monophosphate (AMP), norepinephrine (NE), dopamine (DA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) cAMP response element-binding protein (CREB) expression and B-cell lymphoma 2 (Bcl-2) expression were measured. The brain’s cognitive functions (Spontaneous locomotor activity, Rotarod performance test, Object recognition test) were assessed. B-Car prevented alteration of the brain’s cognitive function in a dose-dependent manner. The histopathological outcomes supported these biochemical evidences. Based on these results, it could be established that B-Car could be assigned to treat the brain’s neurotoxicity consequences of HE via downregualtion of MAPK/NF-κB signaling pathways.

Keywords: beta-carotene, liver injury, MAPK, NF-κB, rat, thioacetamide

Procedia PDF Downloads 28
18 Design and Synthesis of Some Pyrimidine Derivatives as Bruton’s Tyrosine Kinase Inhibitors for Hematologic Malignancies

Authors: Ibrahim M. Labouta, Gina N. Tageldin, Salwa M. Fahmy, Hayam M. Ashour, Mounir A. Khalil, Tamer M. Ibrahim, Nefertiti A. El-Nikhely

Abstract:

Bruton’s tyrosine kinase (BTK) is a critical effector molecule in B cell antigen receptor (BCR) signaling transduction. It regulates B cell proliferation, development and survival. Since BTK is widely expressed in many B cell leukaemias and lymphomas, targeting BTK by small molecules inhibitors became an attractive idea as new treatment modalities for B cell mediated hematologic malignancies. Ibrutinib is the 1st generation BTK inhibitor, approved by FDA for treatment of relapsed mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). It binds irreversibly to the unique cysteine (Cys481) within the ATP-binding pocket of BTK. Besides ibrutinib, many irreversible covalent BTK inhibitors comprising pyrimidine nucleus such as spebrutinib (phase IIb) showed high selectivity and potency when compared to it. In this study, the designed compounds were based on 5-cyano-2-methylsulfanyl pyrimidine core and decorated with electrophilic warheads which are essential for the optimal activity for targeted covalent inhibition (TCI). However, modifications at pyrimidine C4 or C6 were made by introduction of substituted amines which are provided to behave differently. The synthesized derivatives were evaluated for their anticancer activity in leukemia cell lines (e.g. THP-1). Results showed that, some derivatives exhibited antiproliferative activity with IC50 ranged from 5-50 μM, The in vitro enzymatic inhibitory assay for these compounds against BTK is still under investigation. Nevertheless, we could conclude from the initial biological screening that, the synthesized 4 or 6-subsitituted aminopyrimidines represent promising and novel antileukemic agents. Meanwhile, further studies are still needed to attribute this activity through targeting BTK enzyme and inhibition of BCR signaling pathway.

Keywords: BTK inhibitors, hematologic malignancies, structure based drug design (SBDD), targeted covalent inhibitors (TCI)

Procedia PDF Downloads 63
17 Epstein, Barr Virus Alters ATM-Dependent DNA Damage Responses in Germinal Centre B-Cells during Early Infection

Authors: Esther N. Maina, Anna Skowronska, Sridhar Chaganti, Malcolm A. Taylor, Paul G. Murray, Tatjana Stankovic

Abstract:

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of human tumours of B-cell origin. The demonstration that a proportion of Hodgkin lymphomas and all Burkitt’s lymphomas harbour EBV suggests that the virus contributes to the development of these malignancies. However, the mechanisms of lymphomagenesis remain largely unknown. To determine whether EBV causes DNA damage and alters DNA damage response in cells of EBV-driven lymphoma origin, Germinal Centre (GC) B cells were infected with EBV and DNA damage responses to gamma ionising radiation (IR) assessed at early time points (12hr – 72hr) after infection and prior to establishment of lymphoblastoid (LCL) cell lines. In the presence of EBV, we observed induction of spontaneous DNA DSBs and downregulation of ATM-dependent phosphorylation in response to IR. This downregulation coincided with reduced ability of infected cells to repair IR-induced DNA double-strand breaks, as measured by the kinetics of gamma H2AX, a marker of double-strand breaks, and by the tail moment of the comet assay. Furthermore, we found that alteration of DNA damage responses coincided with the expression of LMP-1 protein. The presence of the EBV virus did not affect the localization of the ATM-dependent DNA repair proteins to sites of damage but instead lead to an increased expression of PP5, a phosphatase that regulates ATM function. The impact of the virus on DNA repair was most prominent 24h after infection, suggesting that this time point is crucial for the viral establishment in B cells. Our results suggest that during an early infection EBV virus dampens crucial cellular responses to DNA double-strand breaks which facilitate successful viral infection, but at the same time might provide the mechanism for tumor development.

Keywords: EBV, ATM, DNA damage, germinal center cells

Procedia PDF Downloads 260
16 The Cleavage of DNA by the Anti-Tumor Drug Bleomycin at the Transcription Start Sites of Human Genes Using Genome-Wide Techniques

Authors: Vincent Murray

Abstract:

The glycopeptide bleomycin is used in the treatment of testicular cancer, Hodgkin's lymphoma, and squamous cell carcinoma. Bleomycin damages and cleaves DNA in human cells, and this is considered to be the main mode of action for bleomycin's anti-tumor activity. In particular, double-strand breaks are thought to be the main mechanism for the cellular toxicity of bleomycin. Using Illumina next-generation DNA sequencing techniques, the genome-wide sequence specificity of bleomycin-induced double-strand breaks was determined in human cells. The degree of bleomycin cleavage was also assessed at the transcription start sites (TSSs) of actively transcribed genes and compared with non-transcribed genes. It was observed that bleomycin preferentially cleaved at the TSSs of actively transcribed human genes. There was a correlation between the degree of this enhanced cleavage at TSSs and the level of transcriptional activity. Bleomycin cleavage is also affected by chromatin structure and at TSSs, the peaks of bleomycin cleavage were approximately 200 bp apart. This indicated that bleomycin was able to detect phased nucleosomes at the TSSs of actively transcribed human genes. The genome-wide cleavage pattern of the bleomycin analogues 6′-deoxy-BLM Z and zorbamycin was also investigated in human cells. As found for bleomycin, these bleomycin analogues also preferentially cleaved at the TSSs of actively transcribed human genes. The cytotoxicity (IC₅₀ values) of these bleomycin analogues was determined. It was found that the degree of enhanced cleavage at TSSs was inversely correlated with the IC₅₀ values of the bleomycin analogues. This suggested that the level of cleavage at the TSSs of actively transcribed human genes was important for the cytotoxicity of bleomycin and analogues. Hence this study provided a deeper understanding of the cellular processes involved in the cancer chemotherapeutic activity of bleomycin.

Keywords: anti-tumour activity, bleomycin analogues, chromatin structure, genome-wide study, Illumina DNA sequencing

Procedia PDF Downloads 53