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Ultraviolet radiation-induced carcinogenesis: Mechanisms and experimental models
Karthikeyan Ramasamy, Mohana Shanmugam, Agilan Balupillai, Kanimozhi Govindhasamy, Srithar Gunaseelan, Ganesan Muthusamy, Beualah Mary Robert, Rajendra Prasad Nagarajan
January-March 2017, 8(1):4-19
Ultraviolet radiation (UVR) is a very prominent environmental toxic agent. UVR has been implicated in the initiation and progression of photocarcinogenesis. UVR exposure elicits numerous cellular and molecular events which include the generation of inflammatory mediators, DNA damage, epigenetic modifications, and oxidative damages mediated activation of signaling pathways. UVR-initiated signal transduction pathways are believed to be responsible for tumor promotion effects. UVR-induced carcinogenic mechanism has been well studied using various animal and cellular models. Human skin-derived dermal fibroblasts, epidermal keratinocytes, and melanocytes served as excellent cellular model systems for the understanding of UVR-mediated carcinogenic events. Apart from this, scientists developed reconstituted three-dimensional normal human skin equivalent models for the study of UVR signaling pathways. Moreover, hairless mice such as SKH-1, devoid of Hr gene, served as a valuable model for experimental carcinogenesis. Scientists have also used transgenic mice and dorsal portion shaved Swiss albino mice for UVR carcinogenesis studies. In this review, we have discussed the current progress in the study on ultraviolet B (UVB)-mediated carcinogenesis and outlined appropriate experimental models for both ultraviolet A- and UVB-mediated carcinogenesis.
  13 4,746 693
Phytochemicals as modulators of ultraviolet-b radiation induced cellular and molecular events: A review
Thangaiyan Radhiga, Balupillai Agilan, Umar Muzaffer, Ramasamy Karthikeyan, Govindasamy Kanimozhi, VI Paul, Nagarajan Rajendra Prasad
January-March 2016, 7(1):2-12
Ultraviolet (UV) radiation is a very prominent environmental toxic agent. Particularly, UVB (280–320 nm – short wave) wavelength penetrates the epidermis and is completely absorbed in the upper dermis, whereas UVA (320–400 nm - long wave) penetrates to the deeper dermis. UVA is a relatively weak carcinogen than UVB because of its weak strength as a tumor initiating agent. UVB exposure elicits adverse effect which includes sunburn, basal and squamous cell carcinoma, melanoma, cataracts, photoaging of the skin and immunosuppression. Increased ozone depletion and modern lifestyle has increased the amount of UV exposure, and this consequently led to a surge in the incidence of skin cancer. UVB-irradiation acts as both tumor initiator and tumor promoter in animal models. UVB-initiated signal transduction pathways are believed to be responsible for tumor promotion effects. Variety of cellular changes, which includes activation of transcription factors and protein kinases were altered during acute and chronic UVB-exposure. All these events leads to skin cancer development involving DNA damage, inflammation, immunosuppression, epidermal hyperplasia, cell cycle dysregulation, depletion of antioxidant–defenses, and reactive oxygen species generation. An epidemiological study shows that human beings consuming varieties of vegetables and fruits are protected from UVB induced carcinogenesis. In the recent years, number of experimental evidences showed that natural nutraceuticals and phytoceuticals are vital targets for UVB-mediated cellular and molecular events and prevents cellular milieu from UVB mediated health effects. In this review, we have discussed the current progress in the study on UVB-mediated signaling that can be exploited as targets for phytochemicals.
  12 3,891 593
Magnetic hyperthermia therapy: An emerging modality of cancer treatment in combination with radiotherapy
Neena Girish Shetake, Murali M.S Balla, Amit Kumar, Badri Narain Pandey
January-March 2016, 7(1):13-17
Magnetic hyperthermia therapy (MHT) involves heat generation using magnetic nanoparticles (MNPs) in response to an externally applied alternating current magnetic field. These MNPs can be specifically targeted to the tumor site for homogenous heating. Compared to MHT, conventional methods of HT cause heterogeneous heating of tumor and thus poor efficacy of cancer treatment. MHT has also been shown to effectively eliminate the highly chemo- and radio-resistant cancer stem cells in the tumor mass. Due to their diagnostic capability as well as heat-induced cancer cell killing ability, extensive research has been carried out to develop MNPs as potential cancer theranostic agent. The major focus of MNP research has been to design MNPs formulations for efficient targeting, increased colloidal stability, effective heat generation, and minimal inherent toxicity. A few recent MNPs formulations meet some of the required features and showed promising results in preclinical and clinical studies. HT applied through conventional modes has been combined with chemo- and radiotherapy, owing to its ability to increase oxygenation and drug supply due to vasodilation but has shown a limited success in clinic. However, a great hope has arisen from the MNPs to make combinatorial therapies more successful, not only because of the many advantages of MNPs mentioned but also due to their potential for targeted delivery of a range of anti-cancer drugs and radiosensitizing agents.
  11 4,365 671
Modified comet assays for the detection of cyclobutane pyrimidine dimers and oxidative base damages
Ganesan Muthusamy, Agilan Balupillai, Kanimozhi Govindasamy, Karthikeyan Ramasamy, Veeramani Kandan Ponniresan, Illiyas Magbool Malla, Rajendra Prasad Nagarajan
January-March 2017, 8(1):82-86
The comet assay (also known as single-cell gel electrophoresis) is a technique for the detection of DNA damage at the level of the individual cell. It is a versatile, relatively simple to perform and sensitive method. Although most investigations make use of its ability to measure DNA single-strand breaks, modifications to the method allow detection of cyclobutane pyrimidine dimers (CPDs), crosslinks, base damage, and apoptotic nuclei. Many investigators also interested in examining the DNA damage as a function of time after exposure to a known genotoxic agent. Here, we present a procedure of comet assay for the detection of DNA strand breaks, base damages, and CPDs that can be used to measure DNA damage during toxicity, oxidative stress, and ultraviolet radiation exposure and it can be applied in human toxicological biomonitoring scenarios.
  9 2,459 335
Current status of radiation countermeasures for acute radiation syndrome under advanced development
Vijay K Singh, Oluseyi O Fatanmi, Paola T Santiago, Madison Simas, Briana K Hanlon, Melissa Garcia, Stephen Y Wise
January-March 2018, 9(1):13-27
The availability of safe and effective radiation countermeasures for the military and civilian population represents a significant unmet medical need. To expedite the development of countermeasures for life-threating situations, the United States Food and Drug Administration (US FDA) has implemented the “Animal Rule” which applies to the development and evaluation of drugs and biologics to reduce or prevent life-threatening conditions caused by exposure to lethal or permanently disabling agents where human efficacy trials are neither feasible nor ethical. In addition, the FDA has introduced several incentives (fast track, orphan drug status, and emergency use authorization [EUA]) to attract drug sponsors to develop such agents for human use. Repurposing is vital to make drugs available for life-threatening conditions. Drugs are commonly repurposed for new indications not originally envisioned. By repurposing a drug, it can be made available for human use much quicker, but this pathway also involves issues such as intellectual property rights as corporations are reluctant to expose their blockbuster pharmaceuticals to additional scientific scrutiny. Two radiomitigators for hematopoietic acute radiation syndrome (H-ARS) (Neupogen and Neulasta) have been approved by the FDA through repurposing. The EUA is a legal means for the FDA to approve new drugs or new indications for the previously approved drugs for use during a declared emergency and is a valid way to expedite drug development. Several promising agents with and without FDA investigational new drug (IND) status for ARS are under advanced development. In the next few years, we expect that the FDA will approve a few radioprotectors for H-ARS as well as gastrointestinal ARS via Animal Rule.
  5 3,409 502
Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in breast cancer cell line
Ahmad Yarmohamadi, Jahanbakhsh Asadi, Roghaye Gharaei, Mostafa Mir, Alireza Khoshbin Khoshnazar
April-June 2018, 9(2):86-92
Purpose: Valproic acid (VPA) is used mainly for the treatment of epilepsy and other seizure disorders, however, it is known to be one of histone deacetylase (HDAC) inhibitors. HDACIs have represented roles in radiation-sensitizing of cancer cells. This study is aimed to study to evaluate the radiosensitizing capability of VPA in MCF-7 breast cancer cell line. Materials and Methods: Cell viability and apoptosis were assayed using MTT and TUNEL assays, respectively and caspase-8 and caspase-9 activities were measured by commercially available kits. Results: Our finding showed that pre treatment of cells with VPA, notably enhanced apoptotic cell death in MCF-7 cell line. Our results showed that VPA sensitizes cancer cells against radiation. Conclusion: Valproic acid could be a beneficial radio-sensitizer in breast cancer radiotherapy.
  4 1,504 210
Carcinogenic risk from low-dose radiation exposure is overestimated
Kaushala P Mishra
January-March 2017, 8(1):1-3
  3 2,642 383
Mass attenuation coefficient and its photon interaction derivables of some skeletal muscle relaxants
HC Manjunatha
January-March 2016, 7(1):18-26
Context: The study of photon interactions with biological materials is essential in radiation medicine and biology, nuclear technology and space research, since radioactive sources are used. Aims: A study of mass attenuation coefficient, effective atomic numbers (Zeff) and electron density of some commonly used skeletal muscle relaxants. Materials and Methods: We have measured the mass attenuation some commonly used skeletal muscle relaxants such as tubocurarine chloride, gallamine triethiodide, pancuronium bromide, suxamethonium bromide and mephenesin for various gamma sources of energy ranging from 84keV to 1330 keV (170Tm, 57Co, 141Ce, 203Hg, 51Cr, 113Sn, 22Na, 137Cs, 60Co, 22Na and 60Co). The measured values agree with the theoretical values. The effective atomic numbers (Zeff) and electron density (Ne) of commonly used skeletal muscle relaxants for total and coherent, incoherent, photoelectric absorption, pair production in atomic and nuclear field photon interaction have been computed in the wide region 1keV to 100GeV using an accurate database of photon-interaction cross sections and the WinXCom program. Results: The significant variation of Zeff and Nel is due to the variations in the dominance of different interaction process in different energy regions. A comparison is also made with the single values of the Zeff and Nel provided by the program XMuDat. We have also calculated CT numbers, kerma values relative to air and dose rate for relaxants which are also not remaining constant with energy. Conclusions: The computed data of mass attenuation coefficient, effective atomic numbers (Zeff) and electron density and CT numbers in the low energy region helps in visualizing the image of the biological samples and precise accuracy in treating the inhomogenity of them in medical radiology. The calculated kerma values relative to air and dose rate for relaxants are useful in radiation medicine.
  3 3,252 331
Evaluation of cyclophosphamide-induced genotoxicity and cytotoxicity in cultured human lymphocytes
Ravindra M Samarth, Tooba Khan, Shweta Srivas, Pradyumna K Mishra, Rajnarayan R Tiwari
January-March 2018, 9(1):28-32
Aim: The present study was aimed to examine and evaluate the genotoxicity and cytotoxicity induced by different doses of cyclophosphamide (CP) in normal healthy cultured human peripheral blood lymphocytes. Materials and Methods: Genotoxicity and cytotoxicity was evaluated through mitotic index (MI), chromosomal aberrations, micronuclei frequency, and colony formation assay (plating efficiency [PE] and survival fraction), respectively. Results: It has been observed that CP (1, 2.5, and 5 μg/ml)) induced a dose-dependent increase in chromosomal aberrations and micronuclei frequencies in cultured human peripheral blood lymphocyte as compared to normal. A significant increase was observed in the percentage of aberrant cells and dicentrics/exchanges at 1 and 2.5 μg/ml CP and aberrant cells, breaks, fragments, and dicentrics/exchanges at 5/μg/ml CP. A dose-dependent decrease in values of MI and nuclear division index was also observed in CP-treated group. The frequency of micronuclei in binucleated cells showed a dose-dependent increase. In colony formation assay, PE and surviving fraction values showed significant (P < 0.001) and dose-dependent decrease in the CP treatment groups. Conclusion: The results of present study suggest that CP has genotoxic and cytotoxic effect on cultured human lymphocytes.
  3 1,820 257
Bystander response triggered by doxorubicin-killed dead cells contributes to acquire drug resistance but increasing radiosensitivity In vitro
Abhay Puthli, Reeta Tiwari, Kaushala Prasad Mishra
October-December 2016, 7(4):103-111
Introduction: A bystander effect typically refers to the death, altered growth or damage of cells that have not directly received chemotherapy or irradiation. Chemotherapeutic drugs like doxorubicin cause a drastic increase in the number of dead cells more towards the periphery and low towards the centre of the tumor prompting us to test for the existence of a bystander effect in view of the tumor microenvironment. Materials and Methods: HeLa cervical cancer cells were acutely exposed to doxorubicin to trigger cell death. Bystander HeLa cells in varying amounts were co cultured with fix amount of dead cells. The surviving mutant clones were isolated by serial culturing and checked for morphology, growth pattern and resistance to doxorubicin or radiation. Results: Co-culture results showed, growth arrest, SA-γ-galactosidase activity, an enlarged cell size, collectively indicating a premature senescent state. Up regulation of p53 and γH2AX indicated a DNA damage response pathway. Co-culturing of a fixed number of dead cells with increasing number of bystander cells showed highest number of clones formed in least number of bystander cells. The individual clones obtained were morphologically altered, reduced proliferation and resistant to doxorubicin. Conversely, clones were sensitive to γ radiation compared to control HeLa cells. Conclusion: The results suggest that dead cells conferred significant resistance towards drug but not radiation in cloned bystander tumor cells. This point to possible mechanism of drug resistance in vitro, which might explain the success of radiation therapy and cause of frequent tumor recurrence observed in patients undergoing chemotherapy.
  3 1,735 160
DNA double-strand break repair in mammals
Monica Pandey, Sathees C Raghavan
April-June 2017, 8(2):93-97
Failure in repair of DNA double-strand breaks (DSBs) could result in various disorders in mammals including cancer. Among various exogenous agents, radiation is one of the primary causes for induction of DSBs. Homologous recombination, nonhomologous end-joining, and a less efficient microhomology-mediated end-joining are responsible for repair of DSBs to ensure the genomic integrity and stability. This review highlights DNA damage response (DDR) induced following various insults to the genome and how the DNA repair mechanisms have evolved to restore genomic integrity. We also briefly discuss the potential therapeutic targets associated with DDR and DSB repair and novel inhibitors developed against such targets and their well-defined mechanism of action, which may increase sensitivity to traditional radio- and chemo-therapeutic modalities.
  3 4,610 616
Radiation oxidative stress in cancer induction and prevention
Prabodha Kumar Meher, Kaushala Prasad Mishra
January-March 2017, 8(1):44-52
Exposure of cells to ionizing radiation causes generation of intracellular reactive oxygen species (ROS) which are implicated in the mechanism of carcinogenesis. Molecular steps involved in the transformation of normal cells to cancer cells have been enigmatic but generally believed to arise from aberration in cellular redox homeostasis. In normal cell function, a delicate balance is maintained between ROS generated in the metabolic process and level of endogenous antioxidant defense. ROS are known to regulate various cellular functions, such as cell division, signal transduction, and apoptosis. Cells experience oxidative stress when excess production of ROS occurs inside a cell upon exposure to external stressor agents. This redox imbalance affects the cellular functions due to DNA strand breaks, chromosomal aberrations, gene mutations, alteration in signal transduction, and inhibition of apoptosis leading to induction of cancer and other diseases. Radiation-induced ROS are involved in initiation and promotion of carcinogenesis. Therefore, detoxification of ROS by exogenous antioxidants including dietary polyphenols offers an important strategy for cancer prevention. Recent research results have shown that resistance of cancer stem cells to therapies is linked to low level of ROS. Interestingly, in vitro and in vivo experiments have reported that radiotherapy- and chemotherapy-induced ROS in cytosol sensitize the tumor cells to death, resulting in tumor growth retardation. This review is an attempt to delineate mechanisms of ROS in carcinogenesis and prevention by dietary compounds. Natural polyphenols and dietary antioxidants hold potential to prevent cancer. Interventions in ROS-mediated signal alteration, apoptosis activation, and modulation of epigenetic processes may offer effective cancer prevention strategy.
  3 3,095 428
Ellagic acid radiosensitizes tumor cells by evoking apoptotic pathway
Vidhula R Ahire, KP Mishra
July-September 2016, 7(3):71-78
Cancer causes millions of deaths each year globally. In most patients, the cause of treatment failure is found associated with the resistance to chemotherapy and radiotherapy. The development of tumor cell resistance evokes multiple intracellular molecular pathways. In addition, the limitation in treatment outcome arises due to unintended cytotoxic effects of the synthetic anticancer drugs to normal cells and tissues. Considerable focus of research is, therefore, devoted to examine plant-based herbal compounds which may prove potential anticancer drug for developing effective cancer therapy. Research results from our laboratory have shown that ellagic acid (EA), a natural flavonoid displays enhanced tumor toxicity in combination with gamma radiation to many types of cancers in vitro as well as in vivo. Studies on the underlying mechanisms of toxicity suggest that EA employs the cellular signaling pathways in producing the observed effects. This paper gives an account of molecular mechanisms of EA-induced apoptosis process in tumor cytotoxicity. It is suggested that EA acts as a novel radiosensitizer for tumors and a radioprotector for normal cells which may offer a novel protocol for cancer treatment.
  3 3,050 355
Understanding the basic role of glycocalyx during cancer
Yogendrakumar Harivansh Lahir
July-September 2016, 7(3):79-84
Metastasis or cancer is a functional, molecular and structural disorder which has been an unsolved and fatal mystery and leads to death in most of the individuals suffering from it in spite of the advances made in biomedical and oncological fields. Structurally a tissue consists of cells enclosed by glycocalyx (partially or completely), extracellular matrix incorporating lymphatic and mircovessels. There is a specific amount of glycocalyx sandwiched between extracellular cell matrix and cell membrane depending on the type of the tissue and cell and their location in the biosystems. The common constituents of glycocalyx include biomolecules such as glycolipids, glycoproteins, and oligosaccharides; the glycoproteins are trans-membrane proteins. Any impact due to the interaction between inter- and/or intra-cellular biomolecules or any expected xenobiotics affect extracellular matrix, glycocalyx, cell membrane, cell organelles; these are the prime targets for the investigation related to metastasis. Somehow or the other the glycocalyx has attracted relative less attention of the researchers. The various aspects of the prometastatic interactions involve ligand-receptors, integrins, and other cellular receptors; glycocalyx has its role in such interactions. There are changes in the physicochemical parameters of glycocalyx which affect the cell membrane adversely. These result in malfunctioning of cell signaling, cell proliferation, cell migration, etc. There have been relatively less reports on the structural and functional changes in glycocalyx specifically related to circulating tumor cells and the cancerous cells of organs such as ovary, breast tissue, lungs, and hepatic tissues. In this presentation, an effort is made to review and evaluate the changes in glycocalyx during such interactions between the glycocalyx and the prometastatic molecules.
  3 3,540 368
An audit of setup reproducibility in radiotherapy of head and neck cancers
Mranalini Verma, Abdul Aziz Sait, SK Senthil Kumar, KJ Maria Das, Punita Lal, Shaleen Kumar
July-September 2016, 7(3):85-89
Background: The use of a customized immobilization thermoplastic mask is essential to compute clinical target volume (CTV) to planning target volume (PTV) margins. Purpose: The purpose of this study was to audit setup reproducibility in head and neck cancers (HNCs) since commencing an intensity modulated radiotherapy (IMRT) program. Patients and Methods: Patients for IMRT of HNC were immobilized using either a plain "S" type mask ("S") or with a customized reenforced support at nasion and chin ("S"-NC) or an extended "U" type mask ("U"- NC), for head (H) and neck (N) regions, following radiotherapy planning contrast-enhanced computed tomography scans used to generate digital reconstructed radiographs (DRRs) at 0° (anteroposterior [A-P]) and 270° (lateral) on which match structures were contoured. Orthogonal MV portal images (PIs), A-P, and lateral were obtained. PIs were matched with the DRRs to obtain the setup variations, and the systemic (∑) and random errors (σ) to calculate PTV margins using the van Herk formula (2.5∑ +0.7σ). Results: Thirty-three patients provided 226 paired PIs with matching done separately for HNC regions. PTV margins for mediolateral, A-P, and craniocaudal directions for the head region were 3, 4, and 5 mm for "S"; 3, 4, and 3 mm for "S"-NC; and 3, 2, and 2 mm for extended "U"- NC type masks, respectively. For neck region, PTV margins were 4, 8, and 5 mm for "S"; 3, 5, and 3 mm for "S"-NC; and 4, 5, and 2 mm for extended "U"- NC type masks. Conclusions: These audits provide the necessary confidence to decrease population-based CTV to PTV margins.
  2 2,209 254
Early and late changes in radiation-induced gene expression arrays following radioprotection with amifostine
Thomas M Seed, Vijay K Singh, Briana K Hanlon
January-March 2019, 10(1):44-57
Aims and Objectives: The study objective was to investigate differential gene expression in lymphohematopoietic tissues (spleens) of mice injected with amifostine and exposed to sublethal doses of 60Co γ-radiation. Materials and Methods: Differential cDNA gene expression arrays were used to examine early- (1 day) and late-occurring (63 days) changes in C3H/HeN mice that were administered either amifostine (100 mg/kg) or vehicle 30 min prior to exposure. Results: Sublethal irradiation initiated both early- and late-arising gene responses that were both specific and global in nature, with some significantly modified by amifostine. Of the early changes, ~15% of the genes were upregulated, whereas a comparable fraction was downregulated by irradiation. Notably, amifostine prophylaxis resulted in significant dampening of irradiation-related gene activity. Late-occurring changes were characterized by a reduction in fractional size (~11%) of upregulated genes, along with a corresponding increase of the downregulated fraction (~17%). Again, amifostine prophylaxis resulted in a significant dampening of gene activity, but only for downregulated genes. A cohort of pr oto-oncogenes responded comparably to the entire group of arrayed genes but with several notable exceptions. Differences in gene expression induced by sublethal whole-body radiation exposure were observed here within the splenic tissues of mice, and amifostine prophylaxis significantly altered patterns of gene expression within a sizable fraction of the arrayed genes. Conclusion: This study continues to illustrate the utility of differential cDNA array assays in identifying and dissecting critical gene events (e.g., hematopoietic growth factors and associated proto-oncogenes) altered by irradiation and by the radioprotective pharmacologic amifostine.
  2 895 148
Acute radiation syndrome: An update on biomarkers for radiation injury
Vijay K Singh, Paola T Santiago, Madison Simas, Melissa Garcia, Oluseyi O Fatanmi, Stephen Y Wise, Thomas M Seed
October-December 2018, 9(4):132-146
The possible detonation of a radiological dispersal device or improvised nuclear device in a metropolitan city, or the accidental exposures to a radiation source, nuclear accidents, or the all-to-often threats of radiological/nuclear terrorism have led to the urgent need to develop essential analytic tools to assess such radiation exposures, especially radiation doses to exposed individuals. This exposure-assessing work using biological samples, and discipline, is known as biodosimetry. As of late, this field has progressed significantly as it has made use of the advances within newer areas of biologic analytics, namely omics (genomics, proteomics, metabolomics, and transcriptomics), lymphocyte kinetics, optically stimulated luminescence, and electron paramagnetic resonance technology in addition to conventional cytogenetic techniques. The use of automated high throughput platforms and the planning for laboratory surge capacity during the time of need are the latest developments in the field of biomarkers for biodosimetry. Such biomarkers are also needed for radiation exposure/dose conversion estimates that are essential for the development and application of radiation countermeasures, from animals to humans and that are currently being developed following the US Food and Drug Administration Animal Rule. Here, we present and discuss the current status of various biomarkers for assessing radiation dose after radiation exposure. It is anticipated that with the advent of improved biomarkers and associated biomarker platforms for the acute radiation syndrome, exposed victims can be more efficiently triaged and appropriately treated than is currently allowable. The latest advances in the field, and identify the areas where improvement is needed are also listed and discussed.
  2 1,958 298
Prophylactic strategies to minimize the effect of whole body irradiation on hematopoietic, gastrointestinal and respiratory system leading to morbidity/mortality in animals
Manju Lata Gupta, Savita Verma
January-March 2018, 9(1):4-12
Increase in radionuclide application has gone far and wide in the last many decades; though its usage has benefited the society at large, however occasional unplanned exposure to radiation (terrorist/accidental) has also troubled human life. Exposure of humankind to nuclear disaster, accidental and natural background radiation exposure, has created the need to develop complete understanding of the subject and preparedness for having safe countermeasures. In whole-body radiation exposure scenario, all the three organs are responsible for leading the animal to its death; however, hematopoietic (HP) organ is the first to collapse followed by gastrointestinal (GI) and respiratory systems. Radiation-induced basic damage in these organs follows more or less similar pattern. Derangement starts with radiation-induced reactive oxygen species causing damage to DNA, lipids, and proteins and disturbing their regulatory pathways. However, damage in HP and GI is more rapid and severe due to the presence of highly radiosensitive multipotent stem cells essential to meet the need of high cell turnover rate in these organs. To overcome radiation-induced damage to these vital organs, serious efforts are continued globally to find safe remedial measure.
  2 2,016 237
Mechanism of carcinogenesis after exposure of actinide radionuclides: Emerging concepts and missing links
Rakhee Yadav, Manjoor Ali, Amit Kumar, Badri N Pandey
January-March 2017, 8(1):20-34
Radiation carcinogenesis may be associated with external and/or internal sources of radiation exposure during accidental, occupational, or diagnostic/therapeutic conditions. Most of the radiation carcinogenic events are established after acute doses of low linear energy transfer external radiation. Moreover, the carcinogenic effects of internalized radioisotopes are also reported at their acute/chronic doses. In this regard, actinide radionuclides (like 238U, 239Pu, 232Th, and 241Am) are of great importance as fuel material or waste generated during nuclear power production. These radionuclides may result in incidence of cancer when internalized at high doses while accidental or occupation exposure. Even though the basic carcinogenic mechanism after external or internal radiation exposure remains the same, the magnitude of systemic or target specific radiation effects may vary in these radiation exposure conditions. The majority of the studies investigating biological, carcinogenic, and other health effects of actinide radionuclides are limited only up to quantification of these effects without much mechanistic insights. Moreover, the radiobiological processes, such as bystander effect, genomic instability, and adaptive response, governing the cellular radiosensitivity of targeted/nontargeted cells also need to be studied in the context of carcinogenesis after actinide radionuclides internalization. The review aims to highlight the emerging radiobiological concepts and missing links about actinide radionuclides-induced carcinogenesis. In addition, an overview has been presented about biological and health effects of major actinide radionuclides.
  2 2,347 302
Transgenerational effects of radiation on cancer and other disorders in mice and humans
Taisei Nomura, Larisa S Baleva, Haruko Ryo, Shigeki Adachi, Alla E Sipyagina, Natalya M Karakhan
July-September 2017, 8(3):123-134
Parental exposure of mice to radiation and chemicals causes a variety of adverse effects in the progeny, and the tumor-susceptibility phenotype is transmissible beyond the first postradiation generation. The induced rates of tumors were 100-fold higher than those known for mouse specific locus mutations. There were clear strain differences in the types of naturally-occurring and induced tumors and most of the latter were malignant. Another important finding was that germ-line exposure elicited very weak tumorigenic responses, but caused persistent hypersensitivity in the offspring for the subsequent development of cancer by the postnatal environment. Various disorders were induced in the offspring of mice exposed to radiation. Microsatellite mutations increase dose-dependently and accumulated for 58 generations in the offspring of male parental mice exposed to single dose of X-rays. Changes in gene expression also transmitted to further generations. Radiation-induced genomic instability in germ cells may enhance cancer and other disorders in next generation. In humans, a higher risk of leukemia and birth defects has been reported in the children of fathers who had been exposed to radionuclides in the nuclear reprocessing plants and to diagnostic radiation. These findings have not been supported in the children of atomic bomb survivors in Hiroshima and Nagasaki, who were exposed to higher doses of atomic radiation. However, long-term monitoring of children by Russian Federation Children's Center of Antiradiation Protection after Chernobyl accident shows higher prevalence of malignant neoplasm, mostly childhood cancer, malformation, and other disorders in the children of residents exposed to contaminated radionuclides (>556 kBq/m2). Persistent accumulation of genomic instability may cause various disorders in a further generation in human. This view will gain support from our mouse experiments, because the induced rate of solid tumors in the offspring of mice exposed to radiation is much higher than that of leukemia.
  2 1,636 201
Radiation carcinogenesis: Mechanisms and experimental models - A meeting report
Nagarajan Rajendra Prasad
April-June 2017, 8(2):114-117
The first International School on Radiation Research (2017) of Society for Radiation Research on the theme of “Radiation Carcinogenesis: Mechanisms and Experimental Models” was held in the Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram, Tamil Nadu, India, during February 2–4, 2017. The school gathered basic/translational scientists and young researchers interested in recent developments in molecular and clinical aspects of cancer and radiation carcinogenesis. The objective of the School was to educate and train the young researchers about the theoretical and practical aspects of radiation carcinogenesis. The renowned faculties from India and aboard delivered expert lectures and conducted practical sessions during the school. The topics ranged from the basics of cancer and carcinogenesis; role of DNA damage and genomic instability in the mechanism of carcinogenesis; heavy metal radionuclides induced carcinogenesis; low-dose radiobiology and risk of cancer; ultraviolet (UV)-induced carcinogenesis; experimental models for carcinogenesis studies, and cancer incidence during cancer radiotherapy. During the practical session, demonstrations were arranged of techniques such as DNA damage, apoptosis, measurement of reactive oxygen species, mitochondrial membrane potential, fluorescence in situ hybridization, animal model of UV carcinogenesis, and histopathological observations of various stages of oral cancer. This report presents a brief overview of the scientific and practical sessions of the school.
  1 2,026 215
Thyroid nodule prevalence among young residents in the evacuation area after fukushima daiichi nuclear accident: Results of preliminary analysis using the official data
Suminori Akiba, Athira Nandakumar, Kenta Higuchi, Mayumi Tsuji, Futoshi Uwatoko
October-December 2017, 8(4):174-179
Introduction: The nuclear accidents at Fukushima Daiichi Nuclear Power Plant released more than 10 EBq (exabecquerel) of the radionuclides into the atmosphere. A primary health concern after the nuclear accident is the internal exposure of children to radioactive iodines, which are known to accumulate in the thyroid, and to cause neoplasm. Fortunately, studies conducted so far have shown that the thyroid doses from internal exposure to 131I were low, and therefore, any excess risk of thyroid cancer among residents is considered unlikely to be detected in the future. Data and Analysis: Approximately half a year after the accident, the Fukushima Health Management Survey was started. It includes the thyroid screening survey using ultrasonography and a program to estimate the individual radiation dose of residents and evacuees. Results and Discussions: The first-round thyroid survey, which was conducted during the period 2011–2013, covered 300,476 young residents, approximately 82% of residents eligible for the survey, and found thyroid nodules in 3990 examinees. The prevalence of nodules in the evacuation zone was similar to that in the nonevacuation zone. The second-round survey, which was conducted during the period 3–6 years after the accident, detected 3788 participants with thyroid nodules among 270,511 examinees (approximately 71% of eligible residents). The prevalence of thyroid nodules in the evacuation zone was significantly higher than that in the rest of area (relative risk = 1.32; 95% confidence interval = 1.19, 1.45). Conclusion: Further studies are necessary to evaluate the scientific significance of present findings.
  1 2,535 256
Inhibitor of nonhomologous end joining can inhibit proliferation of diffuse large B-Cell lymphoma cells and potentiate the effect of ionization radiation
Vidya Gopalakrishnan, Gudapureddy Radha, Sathees C Raghavan, Bibha Choudhary
April-June 2018, 9(2):93-101
Aim: Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive type of non-Hodgkin's lymphoma that accounts for ~40% of all lymphomas. DLBCL is considered to be clinically heterogeneous with highest mortality rate. Recent advances in gene expression profiling helped in identifying different subtypes of DLBCL, and since then, many therapeutic options have been explored to treat DLBCL patients. Although it is effective, a significant proportion of the patients suffer due to drug resistance. One of the potential causes for this could be elevated DNA repair in the resistant cancer cells. Thus, the present study is aimed at investigating the potential of SCR7, a DNA repair inhibitor in inducing cytotoxicity on a DLBCL cell line, and to study its ability to potentiate effect when used in combination with ionizing radiation. Materials and Methods: DLBCL cell line, Standford University Diffuse Histiocytic Lymphoma 8 (SUDHL8) was treated with various concentrations of SCR7, a DNA repair inhibitor that targets nonhomologous DNA end joining. While cytotoxicity induced by SCR7 was evaluated through trypan blue assay and flow cytometry analysis, 5,5',6,6 tetrachloro-1,1',3,3'-tetraethyl benzimidazol-carbocyanine iodide and annexin V-FITC/propidium iodide [PI] double-staining assays were used to study the mechanism of cell death. Modulation in the level of DNA repair and apoptotic proteins following treatment with SCR7 was examined by immunoblotting. Effect of SCR7 on sensitizing radiotherapy was further investigated in the SUDHL8 cells. Results: SCR7 induced cytotoxicity in the DLBCL cell line in a concentration- and time-dependent manner. Cell cycle analysis and annexin V/PI double-staining assay confirmed apoptosis in cells without interfering with cell cycle progression. Change in mitochondrial membrane potential in conjunction with alterations in the levels of apoptotic proteins suggested activation of both intrinsic and extrinsic pathways of apoptosis. Importantly, administration of SCR7 potentiated the effect of radiation upon combination therapy in DLBCL. Conclusion: Our results suggest that SCR7 could be developed as an alternative chemotherapeutic approach against DLBCL and is also effective along with radiotherapy.
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Apurinic/apyrimidinic endonuclease 1 performs multiple roles in controlling the outcome of cancer cells toward radiation and chemotherapeutic agents
Dindial Ramotar, Alain Nepveu
April-June 2018, 9(2):67-78
Many endogenous and exogenous sources produce reactive oxygen species such as superoxide radical anions and hydrogen peroxide that are converted to the highly reactive form, hydroxyl radical. It is this latter species that can damage several macromolecules in the cells, in particular, the DNA to produce a variety of DNA lesions. These DNA lesions include oxidatively damaged purine and pyrimidine bases, as well as single-strand and double-strand breaks. These unrepaired DNA lesions lead to base substitutions, deletions, insertions, and rearrangements of the chromosome, ultimately altering the stability of the genome. Maintaining the integrity of the genome is essential to prevent various diseases such as several types of cancers. There are several DNA repair pathways including base-excision repair (BER), nucleotide-excision repair, mismatch repair, homologous recombination, and nonhomologous end joining that operate in the human cells to prevent genomic instability. Each of these DNA repair pathways consists of multiple enzymes that execute specific function (s). This review focuses on a key enzyme apurinic/apyrimidinic endonuclease 1 (APE1) that belongs to the BER pathway that plays a pivotal role in the removal of modified DNA bases. We provide an overview of the multifaceted roles performed by APE1, which also serves as a redox factor and referred to as redox effector factor 1 (Ref-1) or APE1/Ref-1. In addition, we discuss more recent findings whereby (i) peroxiredoxin 1 controls the redox activity of APE1 and (ii) CUT-like homeobox 1 protein, a transcription factor that binds to DNA and stimulates the DNA repair activities of APE1 to confer resistance to radio- and chemotherapy.
  1 1,553 244
Synchrotron-based X-ray microimaging facility for biomedical research
Ashish Kumar Agrawal, Balwant Singh, Yogesh S Kashyap, Mayank Shukla, SC Gadkari
July-September 2017, 8(3):153-159
This paper reports the development of an X-ray imaging facility on Indus-2, synchrotron source at RRCAT, India and its potential applications in biomedical imaging. Indus-2 is country's first third-generation synchrotron source operating at energy of 2.5 Gev and current ~ 200 mA. It is a source of wide spectrum photon beam with very high flux and brilliance; therefore, it can be used for a variety of research such as spectroscopy, diffraction, imaging, lithography, and radiation processing. The development of X-ray imaging beamline here and implementation of several advanced imaging techniques, such as phase-contrast radiography, laminography, tomography, real-time imaging, and fluorescence imaging, has opened up new opportunities for characterization and study of soft tissue and biomaterials. This state of the art national facility is open to users for research in materials, biomedical and microtomography applications.
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* Source: CrossRef