A Novel Intelligent Hybrid Optimized Analytics and Streaming Engine for Medical Big Data.

Medical data processing is exponentially increasing day by day due to the frequent demand for many applications. Healthcare data is one such field, which is dynamically growing day by day. In today's scenario, an enormous amount of sensing devices and data collection units have been employed to generate and collect medical data all over the world. These healthcare devices will result in big real-time data streams. Hence, healthcare-based big data analytics and monitoring have gained hawk-eye importance but needs improvisation. Recently, machine and deep learning algorithms have gained importance to analyze huge amounts of medical data, extract the information, and even predict the future insights of diseases and also cope with the huge volume of data. But applying the learning models to handle big/medical data streams remains to be a challenge among the researchers. This paper proposes the novel deep learning electronic record search engine algorithm (ERSEA) along with firefly optimized long short-term memory (LSTM) model for better data analytics and monitoring. The experimentations have been carried out using Apache Spark using the different medical respiratory data. Finally, the proposed framework results are contrasted with existing models. It shows the accuracy, sensitivity, and specificity like 94%, 93.5%, and 94% for less than 5 GB dataset, and also, more than 5 GB it provides 94%, 92%, and 93% to prove the extraordinary performance of the proposed framework.

Eye Movement Signal Classification for Developing Human-Computer Interface Using Electrooculogram.

Human-computer interfaces (HCI) allow people to control electronic devices, such as computers, mouses, wheelchairs, and keyboards, by bypassing the biochannel without using motor nervous system signals. These signals permit communication between people and electronic-controllable devices. This communication is due to HCI, which facilitates lives of paralyzed patients who do not have any problems with their cognitive functioning. The major plan of this study is to test out the feasibility of nine states of HCI by using modern techniques to overcome the problem faced by the paralyzed. Analog Digital Instrument T26 with a five-electrode system was used in this method. Voluntarily twenty subjects participated in this study. The extracted signals were preprocessed by applying notch filter with a range of 50 Hz to remove the external interferences; the features were extracted by applying convolution theorem. Afterwards, extracted features were classified using Elman and distributed time delay neural network. Average classification accuracy with 90.82% and 90.56% was achieved using two network models. The accuracy of the classifier was analyzed by single-trial analysis and performances of the classifier were observed using bit transfer rate (BTR) for twenty subjects to check the feasibility of designing the HCI. The achieved results showed that the ERNN model has a greater potential to classify, identify, and recognize the EOG signal compared with distributed time delay network for most of the subjects. The control signal generated by classifiers was applied as control signals to navigate the assistive devices such as mouse, keyboard, and wheelchair activities for disabled people.

The Role of Notch, Hedgehog, and Wnt Signaling Pathways in the Resistance of Tumors to Anticancer Therapies.

Resistance to therapy is the major hurdle in the current cancer management. Cancer cells often rewire their cellular process to alternate mechanisms to resist the deleterious effect mounted by different therapeutic approaches. The major signaling pathways involved in the developmental process, such as Notch, Hedgehog, and Wnt, play a vital role in development, tumorigenesis, and also in the resistance to the various anticancer therapies. Understanding how cancer utilizes these developmental pathways in acquiring the resistance to the multi-therapeutic approach cancer can give rise to a new insight of the anti-therapy resistance mechanisms, which can be explored for the development of a novel therapeutic approach. We present a brief overview of Notch, Hedgehog, and Wnt signaling pathways in cancer and its role in providing resistance to various cancer treatment modalities such as chemotherapy, radiotherapy, molecular targeted therapy, and immunotherapy. Understanding the importance of these molecular networks will provide a rational basis for novel and safer combined anticancer therapeutic approaches for the improvement of cancer treatment by overcoming drug resistance.

Radiation induces EIF2AK3/PERK and ERN1/IRE1 mediated pro-survival autophagy.

Cellular effects of ionizing radiation include oxidative damage to macromolecules, unfolded protein response (UPR) and metabolic imbalances. Oxidative stress and UPR have been shown to induce macroautophagy/autophagy in a context-dependent manner and are crucial factors in determining the fate of irradiated cells. However, an in-depth analysis of the relationship between radiation-induced damage and autophagy has not been explored. In the present study, we investigated the relationship between radiation-induced oxidative stress, UPR and autophagy in murine macrophage cells. A close association was observed between radiation-induced oxidative burst, UPR and induction of autophagy, with the possible involvement of EIF2AK3/PERK (eukaryotic translation initiation factor 2 alpha kinase 3) and ERN1/IRE1 (endoplasmic reticulum [ER] to nucleus signaling 1). Inhibitors of either UPR or autophagy reduced the cell survival indicating the importance of these processes after radiation exposure. Moreover, modulation of autophagy affected lethality in the whole body irradiated C57BL/6 mouse. These findings indicate that radiation-induced autophagy is a pro-survival response initiated by oxidative stress and mediated by EIF2AK3 and ERN1. Abbreviations: ACTB: actin, beta; ATF6: activating transcription factor 6; ATG: autophagy-related; BafA1: bafilomycin A1; CQ: chloroquine; DBSA: 3,5-dibromosalicylaldehyde; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; ERN1: endoplasmic reticulum (ER) to nucleus signaling 1; IR: ionizing radiation; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; 3-MA: 3-methyladenine; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; PARP1: poly (ADP-ribose) polymerase family, member 1; 4-PBA: 4-phenylbutyrate; Rap: rapamycin; ROS: reactive oxygen species; UPR: unfolded protein response; XBP1: x-box binding protein 1.

Mitochondrial biogenesis and metabolic hyperactivation limits the application of MTT assay in the estimation of radiation induced growth inhibition.

Metabolic viability based high throughput assays like MTT and MTS are widely used in assessing the cell viability. However, alteration in both mitochondrial content and metabolism can influence the metabolic viability of cells and radiation is a potential mitochondrial biogenesis inducer. Therefore, we tested if MTT assay is a true measure of radiation induced cell death in widely used cell lines. Radiation induced cellular growth inhibition was performed by enumerating cell numbers and metabolic viability using MTT assay at 24 and 48 hours (hrs) after exposure. The extent of radiation induced reduction in cell number was found to be larger than the decrease in MTT reduction in all the cell lines tested. We demonstrated that radiation induces PGC-1α and TFAM to stimulate mitochondrial biogenesis leading to increased levels of SDH-A and enhanced metabolic viability. Radiation induced disturbance in calcium (Ca2+) homeostasis also plays a crucial role by making the mitochondria hyperactive. These findings suggest that radiation induces mitochondrial biogenesis and hyperactivation leading to increased metabolic viability and MTT reduction. Therefore, conclusions drawn on radiation induced growth inhibition based on metabolic viability assays are likely to be erroneous as it may not correlate with growth inhibition and/or loss of clonogenic survival.

Role of interleukin-6 in cancer progression and therapeutic resistance.

In the last several decades, the number of people dying from cancer-related deaths has not reduced significantly despite phenomenal advances in the technologies related to diagnosis and therapeutic modalities. The principal cause behind limitations in the curability of this disease is the reducing sensitivity of the cancer cells towards conventional anticancer therapeutic modalities, particularly in advance stages of the disease. Amongst several reasons, certain secretory factors released by the tumour cells into the microenvironment have been found to confer resistance towards chemo- and radiotherapy, besides promoting growth. Interleukin-6 (IL-6), one of the major cytokines in the tumour microenvironment, is an important factor which is found at high concentrations and known to be deregulated in cancer. Its overexpression has been reported in almost all types of tumours. The strong association between inflammation and cancer is reflected by the high IL-6 levels in the tumour microenvironment, where it promotes tumorigenesis by regulating all hallmarks of cancer and multiple signalling pathways, including apoptosis, survival, proliferation, angiogenesis, invasiveness and metastasis, and, most importantly, the metabolism. Moreover, IL-6 protects the cancer cells from therapy-induced DNA damage, oxidative stress and apoptosis by facilitating the repair and induction of countersignalling (antioxidant and anti-apoptotic/pro-survival) pathways. Therefore, blocking IL-6 or inhibiting its associated signalling independently or in combination with conventional anticancer therapies could be a potential therapeutic strategy for the treatment of cancers with IL-6-dominated signalling.

COX-2, aspirin and metabolism of arachidonic, eicosapentaenoic and docosahexaenoic acids and their physiological and clinical significance.

Polyunsaturated fatty acids (PUFAs) are vital for normal growth and development and physiological function of various tissues in humans. PUFAs have immunomodulatory actions in addition to their ability to modulate inflammation, vascular reactivity, neurotransmission and stem cell biology. PUFAs and their metabolites possess both pro- and anti-inflammatory properties that underlie their actions and involvement in several diseases. Aspirin, a non-steroidal anti-inflammatory drug (NSAID), possesses both cyclo-oxygenase (COX) and lipoxygenase (LOX) inhibitory action and enhances the production of anti-inflammatory lipoxin A4 {(called as epi-lipoxin A4, aspirin-triggered lipoxins (ATLs))}. In addition, at low doses aspirin may not interfere with the production of prostacyclin (PGI2). Both lipoxin A4 and PGI2 have vasodilator, platelet anti-aggregator and anti-inflammatory actions that may underlie the beneficial actions of aspirin. Paradoxically, other NSAIDs may not have the same actions as that of aspirin on PUFA metabolism. Similar anti-inflammatory compounds are formed from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by the action of aspirin termed as resolvins (from EPA and DHA) and protectins and maresins from DHA. PUFAs: arachidonic acid (AA), EPA and DHA and their various products modulate not only inflammation and immune response but also possess actions on various genes, nuclear factors, cyclic AMP and GMP, G-protein coupled receptors (GPRs), hypothalamic neurotransmitters, hormones, cytokines and enzymes, and interact with nitric oxide, carbon monoxide, and hydrogen sulfide to regulate their formation and action and to form new compounds that have several biological actions. These pleiotropic actions of PUFAs and their metabolites may explain their ability to play a role in several physiological actions and diseases. The big challenge is to harness these actions to prevent and manage clinical conditions.

Per a 10 protease activity modulates CD40 expression on dendritic cell surface by nuclear factor-kappaB pathway.

Serine protease activity of Per a 10 from Periplaneta americana modulates dendritic cell (DC) functions by a mechanism(s) that remains unclear. In the present study, Per a 10 protease activity on CD40 expression and downstream signalling was evaluated in DCs. Monocyte-derived DCs from cockroach-allergic patients were treated with proteolytically active/heat-inactivated Per a 10. Stimulation with active Per a 10 demonstrated low CD40 expression on DCs surface (P < 0·05), while enhanced soluble CD40 level in the culture supernatant (P < 0·05) compared to the heat-inactivated Per a 10, suggesting cleavage of CD40. Per a 10 activity reduced the interleukin (IL)-12 and interferon (IFN)-γ secretion by DCs (P < 0·05) compared to heat-inactivated Per a 10, indicating that low CD40 expression is associated with low levels of IL-12 secretion. Active Per a 10 stimulation caused low nuclear factor-kappa B (NF-κB) activation in DCs compared to heat-inactivated Per a 10. Inhibition of the NF-κB pathway suppressed the CD40 expression and IL-12 secretion by DCs, further indicating that NF-κB is required for CD40 up-regulation. CD40 expression activated the tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), thereby suggesting its involvement in NF-κB activation. Protease activity of Per a 10 induced p38 mitogen-activated protein kinase (MAPK) activation that showed no significant effect on CD40 expression by DCs. However, inhibiting p38 MAPK or NF-κB suppressed the secretion of IL-12, IFN-γ, IL-6 and TNF-α by DCs. Such DCs further reduced the secretion of IL-4, IL-6, IL-12 and TNF-α by CD4(+) T cells. In conclusion, protease activity of Per a 10 reduces CD40 expression on DCs. CD40 down-regulation leads to low NF-κB levels, thereby modulating DC-mediated immune responses.

Modifications of cell signalling and redox balance by targeting protein acetylation using natural and engineered molecules: implications in cancer therapy.

Acetylation of proteins with the addition of an acetyl group on the lysine residue is one of the vital posttranslational modifications that regulate protein stability, function and intracellular compartmentalization. Like other posttranslational modifications, protein acetylation influences many if not all vital functions of the cell. Protein acetylation has been originally associated with histone acetylation regulated by Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC) and was mainly considered to be involved in epigenetic regulation through chromatin remodelling. It is now widely referred to as lysine acetylation orchestrated by lysine acetyl transferase (KAT) and lysine deacetylase (KDAC) and influences many cellular functions. Protein acetylation fine tunes the redox balance and cell signalling in the context of cancer by exerting its control on expression of two very important redox sensors viz. Nrf2 and NF-κB. Accumulating evidences show that inhibitors of deacetylase (KDACi), responsible for cytotoxic effects in cancer cells, mediate their actions by inhibiting the deacetylases, thereby simulating an hyperacetylation state of histone as well as non-histone proteins, similar to the one created by KATs. Emergence of calreticulin (CRT) mediated protein acetylation system using polyphenolic acetates as donors coupled with over expression of CRT has opened new avenues for targeting protein acetylation for improving cancer therapy. Modifiers of protein acetylation are therefore, emerging as a class of anticancer therapeutics and adjuvant as they inhibit growth, induce differentiation and death (apoptosis) differentially in cancer cells and also exhibit chemo-radiation sensitizing potential. Although pre-clinical investigations with many natural and synthetic KDAC inhibitors have been very promising, their clinical utility has so far been limited to certain types of cancers of the hematopoietic system. The future of protein acetylation modifiers appears to depend on the development of newer engineered molecules and their rational combinations that can exploit the differences in the regulation of protein acetylation between tumor and normal cells/tissues.

Protective effect on normal brain tissue during a combinational therapy of 2-deoxy-d-glucose and hypofractionated irradiation in malignant gliomas.

PURPOSE: To investigate the effect of 2-deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolysis, on glioblastoma and the normal brain tissue during combined treatment with hypofractionated radiotherapy. MATERIALS AND METHODS: Twenty patients with malignant gliomas (18 Glioblastoma Multiformae, 2 Anasplastic Astrocytoma grade III) following surgery were treated weekly (once) with 2-DG, (250 mg/kg body weight), followed by 5 Gy of radiation to the tumor bed per fraction for 7 weeks. Clinical evaluation, complete hemogram, and random blood sugar levels were carried out in each cycle. Follow-up computed tomography (CT)/magnetic resonance imaging (MRI) was done to evaluate radiation-induced changes. Kernofsky Performance scale (KPS) was recorded preoperatively; postoperatively, and post-therapy till the last follow-up. RESULTS: Twenty patients were recruited for this trail; 19 of them completed the treatment and 1 discontinued. The survival period ranged between 6 and 36 months after the treatment, with a median survival of 14 months. CT and MRI revealed significant tumor necrosis. Histological evidence from the tissue during reexploration confirms the hypothesis of protective effect of 2-DG on normal brain. KPS was above 80% in majority of the patients, 6 months after the surgery. CONCLUSION: Radiotherapy coupled with 2-DG enhances tumor necrosis selectively and significantly while the normal brain gets relatively protected. This has been reflected in our study both clinically by preservation of quality-of-life and pathologically by retaining the integrity of normal brain architecture.

Extracts of Artemisia annua leaves and seeds mediate programmed cell death in Leishmania donovani.

Leishmaniasis is one of the major tropical parasitic diseases, and the condition ranges in severity from self-healing cutaneous lesions to fatal visceral manifestations. There is no vaccine available against visceral leishmaniasis (VL) (also known as kala-azar in India), and current antileishmanial drugs face major drawbacks, including drug resistance, variable efficacy, toxicity and parenteral administration. We report here that n-hexane fractions of Artemisia annua leaves (AAL) and seeds (AAS) possess significant antileishmanial activity against Leishmania donovani promastigotes, with GI(50) of 14.4 and 14.6 µg ml(-1), respectively, and the IC(50) against intracellular amastigotes was found to be 6.6 and 5.05 µg ml(-1), respectively. Changes in the morphology of promastigotes and growth reversibility analysis following treatment confirmed the leishmanicidal effect of the active fractions, which presented no cytotoxic effect on mammalian cells. The antileishmanial activity was mediated via apoptosis, as evidenced by externalization of phosphatidylserine, in situ labelling of DNA fragments by terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling (TUNEL) and cell-cycle arrest at the sub-G(0)/G(1) phase. High-performance thin-layer chromatography (HPTLC) fingerprinting showed that the content of artemisinin in crude bioactive extracts (~1.4 µg per 100 µg n-hexane fraction) was too low to account for the observed antileishmanial activity. Characterization of the active constituents by GC-MS showed that α-amyrinyl acetate, ß-amyrine and derivatives of artemisinin were the major constituents in AAL and cetin, EINECS 211-126-2 and artemisinin derivatives in AAS. Our findings indicate the presence of antileishmanial compounds besides artemisinin in the n-hexane fractions of A. annua leaves and seeds.

Differences in DNA condensation and release by lysine and arginine homopeptides govern their DNA delivery efficiencies.

Designing of nanocarriers that can efficiently deliver therapeutic DNA payload and allow its smooth intracellular release for transgene expression is still a major constraint. The optimization of DNA nanocarriers requires thorough understanding of the chemical and structural characteristics of the vector-nucleic acid complexes and its correlation with the cellular entry, intracellular state and transfection efficiency. L-lysine and L-arginine based cationic peptides alone or in conjugation with other vectors are known to be putative DNA delivery agents. Here we have used L-lysine and L-arginine homopeptides of three different lengths and probed their DNA condensation and release properties by using a multitude of biophysical techniques including fluorescence spectroscopy, gel electrophoresis and atomic force microscopy. Our results clearly showed that although both lysine and arginine based homopeptides condense DNA via electrostatic interactions, they follow different pattern of DNA condensation and release in vitro. While lysine homopeptides condense DNA to form both monomolecular and multimolecular complexes and show differential release of DNA in vitro depending on the peptide length, arginine homopeptides predominantly form multimolecular complexes and show complete DNA release for all peptide lengths. The cellular uptake of the complexes and their intracellular state (as observed through flow cytometry and fluorescence microscopy) seem to be controlled by the peptide chemistry. The difference in the transfection efficiency of lysine and arginine homopeptides has been rationalized in light of these observations.

Peptidyl prolyl isomerase, Pin1 is a potential target for enhancing the therapeutic efficacy of etoposide.

The peptidyl prolyl isomerase (Pin1) that induces cis-trans isomerization of the peptide bond involving serine/threonine-proline has recently been shown to regulate the activity of many phosphoproteins including the ones involved in damage response pathways. We investigated Pin1 as a potential target for enhancing the efficacy of anticancer therapy by studying the effects of juglone, a Pin1 inhibitor on the cytotoxicity of etoposide (a widely used anticancer drug that targets topoisomerase IIα) in human tumor cell lines. Treatment of cells with juglone synergistically enhanced the cytotoxicity of etoposide (loss of clonogenicity) with a tenfold increase when etoposide treatment preceded juglone exposure. On the other hand, the toxicity was than additive when the treatment protocol was reversed (i.e exposure to juglone followed by etoposide treatment). This suggests that Pin1 inhibition possibly reduces the induction of initial DNA damage by etoposide, which was supported by a decrease in the levels of chromatin bound topoIIα. Increase in the etoposide induced toxicity by juglone appeared to be mainly due to enhanced mitotic cell death linked to cytogenetic damage, although a moderate increase in interphase (apoptotic) death was also evident as revealed by DNA degradation (hypodiploid population and TUNEL assay). Since the level of Pin1 is found to be higher in cancer cells, this enzyme could be a potential target for developing an adjuvant to enhance the efficacy of anticancer therapies.

Cancer biomarkers - current perspectives.

In the recent years, knowledge about cancer biomarkers has increased tremendously providing great opportunities for improving the management of cancer patients by enhancing the efficiency of detection and efficacy of treatment. Recent technological advancement has enabled the examination of many potential biomarkers and renewed interest in developing new biomarkers. Biomarkers of cancer could include a broad range of biochemical entities, such as nucleic acids, proteins, sugars, lipids, and small metabolites, cytogenetic and cytokinetic parameters as well as whole tumour cells found in the body fluid. A comprehensive understanding of the relevance of each biomarker will be very important not only for diagnosing the disease reliably, but also help in the choice of multiple therapeutic alternatives currently available that is likely to benefit the patients. This review provides a brief account on various biomarkers for diagnosis, prognosis and therapeutic purposes, which include markers already in clinical practice as well as various upcoming biomarkers.

Enhancement of radiation and chemotherapeutic drug responses by 2-deoxy-D-glucose in animal tumors.

The development of an approach based on the energy-linked modification of DNA repair and cellular recovery processes using 2-deoxy-D-glucose (2-DG; inhibitor of glycolytic ATP production) has shown promising results in a number of model systems of cancer. Following encouraging results on the tolerance and toxicity (acute as well as late effects) of the combination (2-DG and hypofractionated radiotherapy) in Phase I and II clinical trials, its efficacy is currently under evaluation in Phase III clinical trials for glioma patients. Since heterogeneous physiologic and metabolic status in tumors as well as host-tumor interactions influence the local tumor control, which coupled with systemic disturbances could determine the cure (long-term tumor free survival), investigations on the in vivo responses of tumors to the combined treatment have received considerable attention. This communication provides a brief overview on the in vivo studies related to radio- and chemosensitization of tumors by 2-DG, besides the normal tissue toxicity induced by the combined treatment of 2-DG and radiation or chemotherapeutic drugs.

Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: present status and future prospects.

Higher rates of glucose usage generally correlate with poor prognosis in several types of malignant tumours. Experimental studies (both in vitro and in vivo) have shown that 2-deoxy-D-glucose (2-DG), a glucose analog and glycolytic inhibitor, enhances radiation-induced damage selectively in tumor cells while protecting normal cells, thereby suggesting that 2-DG can be used as a differential radiomodifier to improve the efficacy of radiotherapy. Clinical trials undertaken to study the feasibility, safety, and validity of this suggested approach will be described. Based on 2-DG-induced radiosensitization observed in primary organ cultures of cerebral glioma tissues, clinical trials were designed taking into consideration the radiobiology of gliomas and pharmacokinetics of 2-DG. Phase I/II clinical trials have unequivocally demonstrated that a combination of 2-DG (200-300 mg 2-DG per kg body weight orally administered after overnight fasting, 20 min before irradiation) with large weekly fractions (5 Gy/fraction) of low-LET radiotherapy is well tolerated without any acute toxicity or late radiation damage to the normal brain tissue. Nonserious transient side effects similar to hypoglycemia induced disturbances like restlessness, nausea, and vomiting were observed at the 2-DG doses used. Data from these trials involving more than 100 patients have clearly indicated a moderate increase in the survival, with a significant improvement in the quality of life with clinicopathological evidence of protection of normal brain tissue. A phase III multicentric trial to evaluate the efficacy of the combined treatment is in progress. Directions for future studies are discussed.

Cytotoxicity, radiosensitization, and chemosensitization of tumor cells by 2-deoxy-D-glucose in vitro.

The glucose analog 2-deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolytic ATP production, is the most widely investigated metabolic inhibitor for targeting glucose metabolism. Besides depleting energy in cells, 2-DG has also been found to alter N-linked glycosylation leading to unfolded protein responses and induce changes in gene expression and phosphorylation status of proteins involved in signaling, cell cycle control, DNA repair, calcium influx, and apoptosis. Inhibition of cell proliferation and induction of apoptosis have been observed as cytotoxic effects in a wide variety of tumor cells in vitro, while sensitization of tumor cells to ionizing radiation and certain chemotherapeutic drugs is associated with enhanced mitotic as well as apoptotic cell death induced by the primary therapeutic agent. Therefore, there has been a considerable amount of interest in developing 2-DG as a therapeutic agent or adjuvant in the radiotherapy and chemotherapy of tumors.

Protection of normal cells and tissues during radio- and chemosensitization of tumors by 2-deoxy-D-glucose.

Normal tissue toxicity is one of the major limiting factors in cancer therapy. Damage to normal tissues and critical organs restricts the use of higher therapeutic doses thereby compromising the efficacy. The glucose analog 2-deoxy-D-glucose (2-DG), an inhibitor of glycolytic ATP production has been shown to enhance radiation- and chemotherapeutic drug-induced damage in a number of cancer cells under in vitro and in vivo conditions while sparing or protecting normal cells. This review summarizes current understanding on the protection of normal cells and tissues against radiation- and chemotherapeutic drug-induced damage by 2-DG that makes this glucose analog an ideal adjuvant in cancer therapy.

Differential responses of tumors and normal brain to the combined treatment of 2-DG and radiation in glioablastoma.

2-Deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolysis, enhances radiation damage selectively in tumor cells by modulating damage response pathways resulting in cell death in vitro and local tumor control. Phase I and II clinical trials in patients with malignant glioma have shown excellent tolerance to a combined treatment of orally administered 2-DG and hypofractionated radiotherapy without any acute toxicity and late radiation damage. Phase III efficacy trials are currently at an advanced stage. Re-exploratory surgery performed in 13 patients due to persistent symptoms of elevated ICP and mass effect at different follow-up periods revealed extensive tumor necrosis with well-preserved normal brain tissue adjoining the tumor included in the treatment volume as revealed by a histological examination. These observations are perhaps the first clinical evidences for differential effects of 2-DG on tumors and normal tissues in conformity with earlier in vitro and in vivo studies in normal and tumor-bearing mice.