The Experts below are selected from a list of 96 Experts worldwide ranked by ideXlab platform
Adrienne C Scheck - One of the best experts on this subject based on the ideXlab platform.
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abstract 1440 metabolic therapy reduces expression of pecam 1 cd31 and decreases peritumoral edema in a mouse model of malignant glioma
Cancer Research, 2014Co-Authors: Eric C Woolf, Julie A Charlton, Qingwei Liu, Gregory H Turner, Mark C Preul, Adrienne C ScheckAbstract:Patients with malignant brain tumors have a median survival of approximately one year following diagnosis, regardless of currently available treatments which include surgery followed by radiation and chemotherapy. Improvement in the survival of brain cancer patients requires the design of new therapeutic modalities that take advantage of common phenotypes. One such phenotype is the metabolic dysregulation that is a hallmark of cancer cells. It has therefore been postulated that one approach to treating brain tumors may be by metabolic alteration such as that which occurs through the use of the ketogenic diet (KD). The KD is high-fat, low-carbohydrate diet that induces ketosis and has been utilized for the non-pharmacologic treatment of refractory epilepsy. We and others have shown that this diet enhances survival and potentiates standard therapy in mouse models of malignant gliomas, yet the anti-tumor mechanisms are not fully understood. It has been previously shown that caloric restriction, which induces ketosis, reduces microvessel density in mouse and human brain tumor models, suggesting an anti-angiogenic effect. We now report that in animals fed KetoCal® (KC) (4:1 fat:protein/carbohydrates) ad libitum, peritumoral edema is significantly reduced early in tumor progression when compared to those fed a standard rodent diet (SD). Western blot analysis showed a reduction of platelet endothelial cell adhesion molecule 1 (PECAM1/CD31) in tumors from animals maintained on KC. These results were supported by immunohistochemical staining for CD31 which also revealed abnormal vessel structure in the tumors from animals fed SD but not in those fed KC, suggesting a normalizing effect by the KC. Furthermore gene expression profiling demonstrated that KC decreases expression of a group of genes involved in angiogenesis and vessel structuring including the genes encoding vascular endothelial growth factor B (VEGFB) and angiopoetin 1 receptor (TEK), integrin beta 1 (ITGB1), urokinase-type plasminogen activator (PLAU) and tissue inhibitor of metalloproteases 1 (TIMP1). Taken together our data suggests that KC alters the angiogenic processes involved in malignant progression of gliomas. A greater understanding of the effects of the ketogenic diet as an adjuvant therapy will allow for a more rational approach to its clinical use. Citation Format: Eric C. Woolf, Julie A. Charlton, Qingwei Liu, Gregory Turner, Mark C. Preul, Adrienne C. Scheck. Metabolic therapy reduces expression of PECAM-1/CD31 and decreases peritumoral edema in a mouse model of malignant glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1440. doi:10.1158/1538-7445.AM2014-1440
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the ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma
PLOS ONE, 2012Co-Authors: Mohammed G Abdelwahab, Mark C Preul, Kathryn E Fenton, Jong M Rho, Andy G Lynch, Phillip Stafford, Adrienne C ScheckAbstract:Introduction The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. KetoCal® (KC) is a nutritionally complete, commercially available 4∶1 (fat∶ carbohydrate+protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of refractory pediatric epilepsy. Diet-induced ketosis causes changes to brain homeostasis that have potential for the treatment of other neurological diseases such as malignant gliomas. Methods We used an intracranial bioluminescent mouse model of malignant glioma. Following implantation animals were maintained on standard diet (SD) or KC. The mice received 2×4 Gy of whole brain radiation and tumor growth was followed by in vivo imaging. Results Animals fed KC had elevated levels of β-hydroxybutyrate (p = 0.0173) and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bioluminescent signal from the tumor cells diminished below the level of detection (p<0.0001). Animals were switched to SD 101 days after implantation and no signs of tumor recurrence were seen for over 200 days. Conclusions KC significantly enhances the anti-tumor effect of radiation. This suggests that cellular metabolic alterations induced through KC may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas.
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metabolic therapy reduces expression of pecam cd31 and decreases peritumoral edema in a mouse model of malignant glioma
2012Co-Authors: Eric C Woolf, Julie A Charlton, Qingwei Liu, Gregory H Turner, Mark C Preul, Adrienne C ScheckAbstract:Brain tumors remain one of the most deadly malignant tumors, claiming an estimated 13,000 lives in the US every year. Despite neurosurgical advances and improvements in chemotherapy and radiotherapy, median survival remains at ~12 months. The occurrence and severity of the disease has prompted the investigation of novel therapies that can be utilized as an adjuvant to current standards of care. Alteration of tumor metabolism is one such therapy. The ketogenic diet (KD) is a therapeutic high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. While it is generally accepted that the KD provides a neuroprotective effect, the mechanisms are not fully understood. Our laboratory [2] and others [3] have shown that the KD causes an elevation in blood ketones and extends life in mouse models of brain tumor. Initial gene expression data from these experiments show that the KD alters the expression of genes involved in not only metabolism but other crucial processes involved in tumor progression, including inflammation. We also explored KetoCal® (KC) (Nutricia North America, Gaithersburg, MD, USA), a 4:1 (fat to protein + carbohydrate ratio) formula, which is already approved for human use in other disease states such as refractory epilepsy. In our mouse model of malignant glioma, KC when given in combination with radiation treatment, apparently cured the implanted tumor in 9 out of 11 mice [5]. These exciting results warrant a closer look at the mechanisms underlying the KD. One hallmark of many cancers including brain tumors is increased angiogenesis. The deregulated formation of these tumor blood vessels often renders them highly permeable which can lead to increased peritumoral edema, which increases the overall tumor burden on the brain and reduces the quality of life for patients. The current treatment for edema relies on corticosteroids which results in harsh side effects. Therefore a less toxic alternative therapy is needed to mitigate peritumoral edema in brain tumor patients (6). Our data suggests that KC reduces peritumoral edema, reduces tumor angiogenesis and normalizes blood vessel formation. This data taken together with our previous work suggests that the ketogenic diet may not only enhance radiation therapy but also target tumor angiogenesis and inflammation simultaneously. Further exploration of the KD could provide valuable insight into the anti-tumor mechanisms underlying metabolic therapy. This in turn could lead to ways to enhance current treatment while improving quality of life for patients.
Wolfgang Wintermeyer - One of the best experts on this subject based on the ideXlab platform.
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Structure of 4.5S RNA in the signal recognition particle of Escherichia coli as studied by enzymatic and chemical probing.
RNA, 1996Co-Authors: Georg Lentzen, Hervé Moine, Chantal Ehresmann, Bernard Ehresmann, Wolfgang WintermeyerAbstract:The structure of 4.5s RNA, the Escherichia co/i homologue of the signal recognition particle (SRP) RNA, alone and in the SRP complex with protein P48 (Ffh) was probed both enzymatically and chemically. The molecule is largely resistant against single strand-specific nucleases, indicating a highly base paired structure. Reactivity appears mainly in the apical tetraloop and in one of the conserved internal loops. Although some residues are found reactive toward dimethylsulphate and kethoxal in regions predicted to be unpaired by the phylogenetic secondary structure model of 4.5s RNA, generally the reactivity is low, and some residues in internal loops are not reactive at all. RNase Vl cleaves the RNA at multiple sites that coincide with predicted helices, although the cleavages show a pronounced asymmetry. The binding of protein P48 to 4.5s RNA results in a protection of residues in the apical part of the molecule homologous to eukaryotic SRP RNA (domain IV), whereas the cleavages in the conserved apical tetraloop are not protected. Hydroxyl radical treatment reveals an asymmetric pattern of backbone reactivity; in particular, the region encompassing nucleotides 8082, i.e., the 3’ part of the conserved domain IV, is protected. The data suggest that a bend in the domain IV region, most likely at the central asymmetric internal loop, is an important element of the tertiary structure of 4.5s RNA. Hyperchromiclty and lead cleavage data are consistent with the model as they reveal the unfolding of a higher-order structure between 30 and 40 OC. Protection by protein P48 occurs in this region of the RNA and, more strongly, in the 5’ part of domain IV (nt 28-50, most strongly from 35 to 49). It is likely that P48 binds to the outside of the bent form of 4.5s RNA.
Mark C Preul - One of the best experts on this subject based on the ideXlab platform.
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abstract 1440 metabolic therapy reduces expression of pecam 1 cd31 and decreases peritumoral edema in a mouse model of malignant glioma
Cancer Research, 2014Co-Authors: Eric C Woolf, Julie A Charlton, Qingwei Liu, Gregory H Turner, Mark C Preul, Adrienne C ScheckAbstract:Patients with malignant brain tumors have a median survival of approximately one year following diagnosis, regardless of currently available treatments which include surgery followed by radiation and chemotherapy. Improvement in the survival of brain cancer patients requires the design of new therapeutic modalities that take advantage of common phenotypes. One such phenotype is the metabolic dysregulation that is a hallmark of cancer cells. It has therefore been postulated that one approach to treating brain tumors may be by metabolic alteration such as that which occurs through the use of the ketogenic diet (KD). The KD is high-fat, low-carbohydrate diet that induces ketosis and has been utilized for the non-pharmacologic treatment of refractory epilepsy. We and others have shown that this diet enhances survival and potentiates standard therapy in mouse models of malignant gliomas, yet the anti-tumor mechanisms are not fully understood. It has been previously shown that caloric restriction, which induces ketosis, reduces microvessel density in mouse and human brain tumor models, suggesting an anti-angiogenic effect. We now report that in animals fed KetoCal® (KC) (4:1 fat:protein/carbohydrates) ad libitum, peritumoral edema is significantly reduced early in tumor progression when compared to those fed a standard rodent diet (SD). Western blot analysis showed a reduction of platelet endothelial cell adhesion molecule 1 (PECAM1/CD31) in tumors from animals maintained on KC. These results were supported by immunohistochemical staining for CD31 which also revealed abnormal vessel structure in the tumors from animals fed SD but not in those fed KC, suggesting a normalizing effect by the KC. Furthermore gene expression profiling demonstrated that KC decreases expression of a group of genes involved in angiogenesis and vessel structuring including the genes encoding vascular endothelial growth factor B (VEGFB) and angiopoetin 1 receptor (TEK), integrin beta 1 (ITGB1), urokinase-type plasminogen activator (PLAU) and tissue inhibitor of metalloproteases 1 (TIMP1). Taken together our data suggests that KC alters the angiogenic processes involved in malignant progression of gliomas. A greater understanding of the effects of the ketogenic diet as an adjuvant therapy will allow for a more rational approach to its clinical use. Citation Format: Eric C. Woolf, Julie A. Charlton, Qingwei Liu, Gregory Turner, Mark C. Preul, Adrienne C. Scheck. Metabolic therapy reduces expression of PECAM-1/CD31 and decreases peritumoral edema in a mouse model of malignant glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1440. doi:10.1158/1538-7445.AM2014-1440
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the ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma
PLOS ONE, 2012Co-Authors: Mohammed G Abdelwahab, Mark C Preul, Kathryn E Fenton, Jong M Rho, Andy G Lynch, Phillip Stafford, Adrienne C ScheckAbstract:Introduction The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. KetoCal® (KC) is a nutritionally complete, commercially available 4∶1 (fat∶ carbohydrate+protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of refractory pediatric epilepsy. Diet-induced ketosis causes changes to brain homeostasis that have potential for the treatment of other neurological diseases such as malignant gliomas. Methods We used an intracranial bioluminescent mouse model of malignant glioma. Following implantation animals were maintained on standard diet (SD) or KC. The mice received 2×4 Gy of whole brain radiation and tumor growth was followed by in vivo imaging. Results Animals fed KC had elevated levels of β-hydroxybutyrate (p = 0.0173) and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bioluminescent signal from the tumor cells diminished below the level of detection (p<0.0001). Animals were switched to SD 101 days after implantation and no signs of tumor recurrence were seen for over 200 days. Conclusions KC significantly enhances the anti-tumor effect of radiation. This suggests that cellular metabolic alterations induced through KC may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas.
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metabolic therapy reduces expression of pecam cd31 and decreases peritumoral edema in a mouse model of malignant glioma
2012Co-Authors: Eric C Woolf, Julie A Charlton, Qingwei Liu, Gregory H Turner, Mark C Preul, Adrienne C ScheckAbstract:Brain tumors remain one of the most deadly malignant tumors, claiming an estimated 13,000 lives in the US every year. Despite neurosurgical advances and improvements in chemotherapy and radiotherapy, median survival remains at ~12 months. The occurrence and severity of the disease has prompted the investigation of novel therapies that can be utilized as an adjuvant to current standards of care. Alteration of tumor metabolism is one such therapy. The ketogenic diet (KD) is a therapeutic high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. While it is generally accepted that the KD provides a neuroprotective effect, the mechanisms are not fully understood. Our laboratory [2] and others [3] have shown that the KD causes an elevation in blood ketones and extends life in mouse models of brain tumor. Initial gene expression data from these experiments show that the KD alters the expression of genes involved in not only metabolism but other crucial processes involved in tumor progression, including inflammation. We also explored KetoCal® (KC) (Nutricia North America, Gaithersburg, MD, USA), a 4:1 (fat to protein + carbohydrate ratio) formula, which is already approved for human use in other disease states such as refractory epilepsy. In our mouse model of malignant glioma, KC when given in combination with radiation treatment, apparently cured the implanted tumor in 9 out of 11 mice [5]. These exciting results warrant a closer look at the mechanisms underlying the KD. One hallmark of many cancers including brain tumors is increased angiogenesis. The deregulated formation of these tumor blood vessels often renders them highly permeable which can lead to increased peritumoral edema, which increases the overall tumor burden on the brain and reduces the quality of life for patients. The current treatment for edema relies on corticosteroids which results in harsh side effects. Therefore a less toxic alternative therapy is needed to mitigate peritumoral edema in brain tumor patients (6). Our data suggests that KC reduces peritumoral edema, reduces tumor angiogenesis and normalizes blood vessel formation. This data taken together with our previous work suggests that the ketogenic diet may not only enhance radiation therapy but also target tumor angiogenesis and inflammation simultaneously. Further exploration of the KD could provide valuable insight into the anti-tumor mechanisms underlying metabolic therapy. This in turn could lead to ways to enhance current treatment while improving quality of life for patients.
Thomas N Seyfried - One of the best experts on this subject based on the ideXlab platform.
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the calorically restricted ketogenic diet an effective alternative therapy for malignant brain cancer
Nutrition & Metabolism, 2007Co-Authors: Weihua Zhou, Purna Mukherjee, Michael A Kiebish, William T Markis, John G Mantis, Thomas N SeyfriedAbstract:Malignant brain cancer persists as a major disease of morbidity and mortality in adults and is the second leading cause of cancer death in children. Many current therapies for malignant brain tumors fail to provide long-term management because they ineffectively target tumor cells while negatively impacting the health and vitality of normal brain cells. In contrast to brain tumor cells, which lack metabolic flexibility and are largely dependent on glucose for growth and survival, normal brain cells can metabolize both glucose and ketone bodies for energy. This study evaluated the efficacy of KetoCal®, a new nutritionally balanced high fat/low carbohydrate ketogenic diet for children with epilepsy, on the growth and vascularity of a malignant mouse astrocytoma (CT-2A) and a human malignant glioma (U87-MG). Adult mice were implanted orthotopically with the malignant brain tumors and KetoCal® was administered to the mice in either unrestricted amounts or in restricted amounts to reduce total caloric intake according to the manufacturers recommendation for children with refractory epilepsy. The effects KetoCal® on tumor growth, vascularity, and mouse survival were compared with that of an unrestricted high carbohydrate standard diet. KetoCal® administered in restricted amounts significantly decreased the intracerebral growth of the CT-2A and U87-MG tumors by about 65% and 35%, respectively, and significantly enhanced health and survival relative to that of the control groups receiving the standard low fat/high carbohydrate diet. The restricted KetoCal® diet reduced plasma glucose levels while elevating plasma ketone body (β-hydroxybutyrate) levels. Tumor microvessel density was less in the calorically restricted KetoCal® groups than in the calorically unrestricted control groups. Moreover, gene expression for the mitochondrial enzymes, β-hydroxybutyrate dehydrogenase and succinyl-CoA: 3-ketoacid CoA transferase, was lower in the tumors than in the contralateral normal brain suggesting that these brain tumors have reduced ability to metabolize ketone bodies for energy. The results indicate that KetoCal® has anti-tumor and anti-angiogenic effects in experimental mouse and human brain tumors when administered in restricted amounts. The therapeutic effect of KetoCal® for brain cancer management was due largely to the reduction of total caloric content, which reduces circulating glucose required for rapid tumor growth. A dependency on glucose for energy together with defects in ketone body metabolism largely account for why the brain tumors grow minimally on either a ketogenic-restricted diet or on a standard-restricted diet. Genes for ketone body metabolism should be useful for screening brain tumors that could be targeted with calorically restricted high fat/low carbohydrate ketogenic diets. This preclinical study indicates that restricted KetoCal® is a safe and effective diet therapy and should be considered as an alternative therapeutic option for malignant brain cancer.
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the calorically restricted ketogenic diet an effective alternative therapy for malignant brain cancer
Nutrition & Metabolism, 2007Co-Authors: Weihua Zhou, Purna Mukherjee, Michael A Kiebish, William T Markis, John G Mantis, Thomas N SeyfriedAbstract:Background Malignant brain cancer persists as a major disease of morbidity and mortality in adults and is the second leading cause of cancer death in children. Many current therapies for malignant brain tumors fail to provide long-term management because they ineffectively target tumor cells while negatively impacting the health and vitality of normal brain cells. In contrast to brain tumor cells, which lack metabolic flexibility and are largely dependent on glucose for growth and survival, normal brain cells can metabolize both glucose and ketone bodies for energy. This study evaluated the efficacy of KetoCal®, a new nutritionally balanced high fat/low carbohydrate ketogenic diet for children with epilepsy, on the growth and vascularity of a malignant mouse astrocytoma (CT-2A) and a human malignant glioma (U87-MG).
Eric C Woolf - One of the best experts on this subject based on the ideXlab platform.
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abstract 1440 metabolic therapy reduces expression of pecam 1 cd31 and decreases peritumoral edema in a mouse model of malignant glioma
Cancer Research, 2014Co-Authors: Eric C Woolf, Julie A Charlton, Qingwei Liu, Gregory H Turner, Mark C Preul, Adrienne C ScheckAbstract:Patients with malignant brain tumors have a median survival of approximately one year following diagnosis, regardless of currently available treatments which include surgery followed by radiation and chemotherapy. Improvement in the survival of brain cancer patients requires the design of new therapeutic modalities that take advantage of common phenotypes. One such phenotype is the metabolic dysregulation that is a hallmark of cancer cells. It has therefore been postulated that one approach to treating brain tumors may be by metabolic alteration such as that which occurs through the use of the ketogenic diet (KD). The KD is high-fat, low-carbohydrate diet that induces ketosis and has been utilized for the non-pharmacologic treatment of refractory epilepsy. We and others have shown that this diet enhances survival and potentiates standard therapy in mouse models of malignant gliomas, yet the anti-tumor mechanisms are not fully understood. It has been previously shown that caloric restriction, which induces ketosis, reduces microvessel density in mouse and human brain tumor models, suggesting an anti-angiogenic effect. We now report that in animals fed KetoCal® (KC) (4:1 fat:protein/carbohydrates) ad libitum, peritumoral edema is significantly reduced early in tumor progression when compared to those fed a standard rodent diet (SD). Western blot analysis showed a reduction of platelet endothelial cell adhesion molecule 1 (PECAM1/CD31) in tumors from animals maintained on KC. These results were supported by immunohistochemical staining for CD31 which also revealed abnormal vessel structure in the tumors from animals fed SD but not in those fed KC, suggesting a normalizing effect by the KC. Furthermore gene expression profiling demonstrated that KC decreases expression of a group of genes involved in angiogenesis and vessel structuring including the genes encoding vascular endothelial growth factor B (VEGFB) and angiopoetin 1 receptor (TEK), integrin beta 1 (ITGB1), urokinase-type plasminogen activator (PLAU) and tissue inhibitor of metalloproteases 1 (TIMP1). Taken together our data suggests that KC alters the angiogenic processes involved in malignant progression of gliomas. A greater understanding of the effects of the ketogenic diet as an adjuvant therapy will allow for a more rational approach to its clinical use. Citation Format: Eric C. Woolf, Julie A. Charlton, Qingwei Liu, Gregory Turner, Mark C. Preul, Adrienne C. Scheck. Metabolic therapy reduces expression of PECAM-1/CD31 and decreases peritumoral edema in a mouse model of malignant glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1440. doi:10.1158/1538-7445.AM2014-1440
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metabolic therapy reduces expression of pecam cd31 and decreases peritumoral edema in a mouse model of malignant glioma
2012Co-Authors: Eric C Woolf, Julie A Charlton, Qingwei Liu, Gregory H Turner, Mark C Preul, Adrienne C ScheckAbstract:Brain tumors remain one of the most deadly malignant tumors, claiming an estimated 13,000 lives in the US every year. Despite neurosurgical advances and improvements in chemotherapy and radiotherapy, median survival remains at ~12 months. The occurrence and severity of the disease has prompted the investigation of novel therapies that can be utilized as an adjuvant to current standards of care. Alteration of tumor metabolism is one such therapy. The ketogenic diet (KD) is a therapeutic high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. While it is generally accepted that the KD provides a neuroprotective effect, the mechanisms are not fully understood. Our laboratory [2] and others [3] have shown that the KD causes an elevation in blood ketones and extends life in mouse models of brain tumor. Initial gene expression data from these experiments show that the KD alters the expression of genes involved in not only metabolism but other crucial processes involved in tumor progression, including inflammation. We also explored KetoCal® (KC) (Nutricia North America, Gaithersburg, MD, USA), a 4:1 (fat to protein + carbohydrate ratio) formula, which is already approved for human use in other disease states such as refractory epilepsy. In our mouse model of malignant glioma, KC when given in combination with radiation treatment, apparently cured the implanted tumor in 9 out of 11 mice [5]. These exciting results warrant a closer look at the mechanisms underlying the KD. One hallmark of many cancers including brain tumors is increased angiogenesis. The deregulated formation of these tumor blood vessels often renders them highly permeable which can lead to increased peritumoral edema, which increases the overall tumor burden on the brain and reduces the quality of life for patients. The current treatment for edema relies on corticosteroids which results in harsh side effects. Therefore a less toxic alternative therapy is needed to mitigate peritumoral edema in brain tumor patients (6). Our data suggests that KC reduces peritumoral edema, reduces tumor angiogenesis and normalizes blood vessel formation. This data taken together with our previous work suggests that the ketogenic diet may not only enhance radiation therapy but also target tumor angiogenesis and inflammation simultaneously. Further exploration of the KD could provide valuable insight into the anti-tumor mechanisms underlying metabolic therapy. This in turn could lead to ways to enhance current treatment while improving quality of life for patients.
