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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Παρασκευή 27 Οκτωβρίου 2017
Subcutaneous metastasis from recurrent basaloid squamous cell carcinoma of the esophagus
Journal of Oncology Pharmacy Practice, Ahead of Print.
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A clinical pharmacy pilot within a Precision Medicine Program for cancer patients and review of related pharmacist clinical practice
Journal of Oncology Pharmacy Practice, Ahead of Print.
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Dual mTOR Kinases MLN0128 Inhibitor Sensitizes HR+/HER2+ Breast Cancer Patient-derived Xenografts to Trastuzumab or Fulvestrant
Purpose: Therapeutic strategies against hormonal receptor-positive (HR+)/HER2+ breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR+/HER2+ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2+ breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis. Results: Estrogen acted as a growth-driver of trastuzumab-resistant COH-SC31 tumors, but an accelerator in trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR+/HER2+ PDXs. Combination of dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied with increasing ER-positive cell population in vivo. Instead, MLN0128 in combination with anti-estrogen fulvestrant significantly halted the growth of HR+/HER2+ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo. Conclusion:Compared to the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR+/HER2+ tumors through establishment of two PDXs coupling with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future "co-clinical" trials to tailor personalized medicine in clinical practice.
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Dual mTOR Kinases MLN0128 Inhibitor Sensitizes HR+/HER2+ Breast Cancer Patient-derived Xenografts to Trastuzumab or Fulvestrant
Purpose: Therapeutic strategies against hormonal receptor-positive (HR+)/HER2+ breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR+/HER2+ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2+ breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis. Results: Estrogen acted as a growth-driver of trastuzumab-resistant COH-SC31 tumors, but an accelerator in trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR+/HER2+ PDXs. Combination of dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied with increasing ER-positive cell population in vivo. Instead, MLN0128 in combination with anti-estrogen fulvestrant significantly halted the growth of HR+/HER2+ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo. Conclusion:Compared to the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR+/HER2+ tumors through establishment of two PDXs coupling with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future "co-clinical" trials to tailor personalized medicine in clinical practice.
http://ift.tt/2yYf8qO
Histone deacetylase inhibition enhances the antitumor activity of a MEK inhibitorin lung cancer cells harboring RAS mutations
Non-small-cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatments for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. It has been reported that one way the RAS-ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle. This is through regulation of apoptotic proteins BIM and FASL and cell cycle regulators p21Cip1 and p27 Kip1. We now show that a HDAC inhibitor affects the expression and localization of FOXO proteins and wanted to determine if the combination of a MEK inhibitor with a HDAC inhibitor would increase the sensitivity of NSCLC with KRAS mutation. Combined treatment with a MEK inhibitor and a HDAC inhibitor showed synergistic effects on cell metabolic activity of RAS mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and the cell cycle inhibitors p21Cip1 and p27 Kip1. These results demonstrate that control of FOXOs localization and expression is critical in RAS driven lung cancer cells, suggesting that the dual molecular targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of RAS mutations.
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Selective and concentrated accretion of SN-38 with a CEACAM5-targeting antibody-drug conjugate (ADC), labetuzumab govitecan (IMMU-130)
Labetuzumab govitecan (IMMU-130), an antibody-drug conjugate (ADC) with an average of 7.6 SN-38/IgG, was evaluated for its potential to enhance delivery of SN-38 to human colonic tumor xenografts. Mice bearing LS174T or GW-39 human colonic tumor xenografts were injected with irinotecan or IMMU-130 (SN-38 equivalents ~500 µg or ~16 µg, respectively). Serum and homogenates of tumors, liver, and small intestine were extracted, and SN-38, SN-38G (glucuronidated SN-38), and irinotecan concentrations determined by reversed-phase HPLC. Irinotecan cleared quickly from serum, with only 1-2% injected dose/mL after 5 min; overall, ~20% was converted to SN-38 andSN-38G. At 1 h with IMMU-130, 45-63% injected dose/mL of the SN-38 was in the serum, with >90% bound to the ADC over 3 days, and with low levels of SN-38G. Total SN-38 levels decreased more quickly than the IgG, confirming a gradual SN-38 release from the ADC. Area under the curve analysis found SN-38 levels were ~11- and 16-fold higher in LS174T and GW-39 tumors, respectively, in IMMU-130-treated animals. This delivery advantage is amplified >30-fold when normalized to SN-38 equivalents injected for each product. Levels of SN-38 and SN-38G were appreciably lower in the liver and small intestinal contents in animals given IMMU-130. Based on the SN-38 equivalents administered, IMMU-130 potentially delivers >300-fold more SN-38 to CEA-producing tumors compared to irinotecan, while also reducing levels of SN-38 and SN-38G in normal tissues. These observations are consistent with preclinical and clinical data showing efficacy and improved safety.
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Ceramide nanoliposomes as a MLKL-dependent, necroptosis-inducing, chemotherapeutic reagent in ovarian cancer
Ceramides are bioactive lipids that mediate cell death in cancer cells and ceramide-based therapy is now being tested in dose-escalating phase 1 clinical trials as a cancer treatment. Multiple nanoscale delivery systems for ceramide have been proposed to overcome the inherent toxicities, poor pharmacokinetics and difficult biophysics associated with ceramide. Using the ceramide nanoliposomes (CNL) we now investigate the therapeutic efficacy and signaling mechanisms of this nanoscale delivery platform in refractory ovarian cancer. Treatment of ovarian cancer cells with CNL decreased the number of living cells through necroptosis but not apoptosis. Mechanistically, dying SKOV3 ovarian cancer cells exhibit activation of pseudokinase mixed lineage kinase domain-like (MLKL) as evidenced by oligomerization and relocalization to the blebbing membranes, showing necroptotic characteristics. Knock-down of MLKL, but not its upstream protein kinases such as receptor-interacting protein kinases, with siRNA significantly abolished CNL-induced cell death. Monomeric MLKL protein expression inversely correlated with the IC50 values of CNL in distinct ovarian cancer cell lines, suggesting MLKL as a possible determinant for CNL-induced cell death. Finally, systemic CNL administration suppressed metastatic growth in an ovarian cancer cell xenograft model. Taken together, these results suggest that MLKL is a novel pro-necroptotic target for ceramide in ovarian cancer models.
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miR-20a regulates Fas expression in osteosarcoma cells by modulating Fas promoter activity and can be therapeutically targeted to inhibit lung metastases
The metastatic potential of osteosarcoma cells is inversely correlated to cell surface Fas expression. Downregulation of Fas allows osteosarcoma cells to escape Fas ligand-mediated apoptosis when they enter a Fas ligand-positive microenvironment such as the lung. We have previously demonstrated that miR-20a, encoded by the miR-17-92 cluster, downregulates Fas expression in osteosarcoma. We further demonstrated an inverse correlation between Fas expression and miR-20a expression. However, the mechanism of Fas regulation by miR-20a was still unclear. The purpose of the current study was to evaluate the mechanism of Fas regulation by miR-20a in vitro and test the effect of targeting miR-20a in vivo. We investigated whether miR-20a's downregulation of Fas was mediated by binding to the 3' untranslated region (3'-UTR) of Fas mRNA with the consequent induction of mRNA degradation or translational suppression. We identified and mutated two miR-20a binding sites on the Fas mRNA 3'-UTR. Using luciferase reporter assays, we demonstrated that miR-20a did not bind to either the wild-type or mutated Fas 3'-UTR. By contrast, overexpression of miR-20a resulted in downregulation of Fas promoter activity. Similarly, the inhibition of miR-20a increased Fas promoter activity. The critical region identified on the Fas promoter was between -240 bp and 150 bp. Delivery of anti-miR-20a in vivo using nanoparticles in mice with established osteosarcoma lung metastases resulted in upregulation of Fas and tumor growth inhibition. Taken together, our data suggest that miR-20a regulates Fas expression through the modulation of the Fas promoter and that targeting miR-20a using anti-miR-20a has therapeutic potential.
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HIF2{alpha} targeted RNAi therapeutic inhibits clear cell renal cell carcinoma
Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2α (HIF2α) and that an over-abundance of HIF2α functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2α that utilizes a targeting ligand that selectively binds to integrins αvβ3 and αvβ5 frequently over-expressed in ccRCC. We demonstrate that functional delivery of a HIF2α specific RNAi trigger resulted in HIF2α gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model.
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Histone deacetylase inhibition enhances the antitumor activity of a MEK inhibitorin lung cancer cells harboring RAS mutations
Non-small-cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatments for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. It has been reported that one way the RAS-ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle. This is through regulation of apoptotic proteins BIM and FASL and cell cycle regulators p21Cip1 and p27 Kip1. We now show that a HDAC inhibitor affects the expression and localization of FOXO proteins and wanted to determine if the combination of a MEK inhibitor with a HDAC inhibitor would increase the sensitivity of NSCLC with KRAS mutation. Combined treatment with a MEK inhibitor and a HDAC inhibitor showed synergistic effects on cell metabolic activity of RAS mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and the cell cycle inhibitors p21Cip1 and p27 Kip1. These results demonstrate that control of FOXOs localization and expression is critical in RAS driven lung cancer cells, suggesting that the dual molecular targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of RAS mutations.
http://ift.tt/2iFXMIY
Selective and concentrated accretion of SN-38 with a CEACAM5-targeting antibody-drug conjugate (ADC), labetuzumab govitecan (IMMU-130)
Labetuzumab govitecan (IMMU-130), an antibody-drug conjugate (ADC) with an average of 7.6 SN-38/IgG, was evaluated for its potential to enhance delivery of SN-38 to human colonic tumor xenografts. Mice bearing LS174T or GW-39 human colonic tumor xenografts were injected with irinotecan or IMMU-130 (SN-38 equivalents ~500 µg or ~16 µg, respectively). Serum and homogenates of tumors, liver, and small intestine were extracted, and SN-38, SN-38G (glucuronidated SN-38), and irinotecan concentrations determined by reversed-phase HPLC. Irinotecan cleared quickly from serum, with only 1-2% injected dose/mL after 5 min; overall, ~20% was converted to SN-38 andSN-38G. At 1 h with IMMU-130, 45-63% injected dose/mL of the SN-38 was in the serum, with >90% bound to the ADC over 3 days, and with low levels of SN-38G. Total SN-38 levels decreased more quickly than the IgG, confirming a gradual SN-38 release from the ADC. Area under the curve analysis found SN-38 levels were ~11- and 16-fold higher in LS174T and GW-39 tumors, respectively, in IMMU-130-treated animals. This delivery advantage is amplified >30-fold when normalized to SN-38 equivalents injected for each product. Levels of SN-38 and SN-38G were appreciably lower in the liver and small intestinal contents in animals given IMMU-130. Based on the SN-38 equivalents administered, IMMU-130 potentially delivers >300-fold more SN-38 to CEA-producing tumors compared to irinotecan, while also reducing levels of SN-38 and SN-38G in normal tissues. These observations are consistent with preclinical and clinical data showing efficacy and improved safety.
http://ift.tt/2ze7BVW
Ceramide nanoliposomes as a MLKL-dependent, necroptosis-inducing, chemotherapeutic reagent in ovarian cancer
Ceramides are bioactive lipids that mediate cell death in cancer cells and ceramide-based therapy is now being tested in dose-escalating phase 1 clinical trials as a cancer treatment. Multiple nanoscale delivery systems for ceramide have been proposed to overcome the inherent toxicities, poor pharmacokinetics and difficult biophysics associated with ceramide. Using the ceramide nanoliposomes (CNL) we now investigate the therapeutic efficacy and signaling mechanisms of this nanoscale delivery platform in refractory ovarian cancer. Treatment of ovarian cancer cells with CNL decreased the number of living cells through necroptosis but not apoptosis. Mechanistically, dying SKOV3 ovarian cancer cells exhibit activation of pseudokinase mixed lineage kinase domain-like (MLKL) as evidenced by oligomerization and relocalization to the blebbing membranes, showing necroptotic characteristics. Knock-down of MLKL, but not its upstream protein kinases such as receptor-interacting protein kinases, with siRNA significantly abolished CNL-induced cell death. Monomeric MLKL protein expression inversely correlated with the IC50 values of CNL in distinct ovarian cancer cell lines, suggesting MLKL as a possible determinant for CNL-induced cell death. Finally, systemic CNL administration suppressed metastatic growth in an ovarian cancer cell xenograft model. Taken together, these results suggest that MLKL is a novel pro-necroptotic target for ceramide in ovarian cancer models.
http://ift.tt/2iFFDLx
miR-20a regulates Fas expression in osteosarcoma cells by modulating Fas promoter activity and can be therapeutically targeted to inhibit lung metastases
The metastatic potential of osteosarcoma cells is inversely correlated to cell surface Fas expression. Downregulation of Fas allows osteosarcoma cells to escape Fas ligand-mediated apoptosis when they enter a Fas ligand-positive microenvironment such as the lung. We have previously demonstrated that miR-20a, encoded by the miR-17-92 cluster, downregulates Fas expression in osteosarcoma. We further demonstrated an inverse correlation between Fas expression and miR-20a expression. However, the mechanism of Fas regulation by miR-20a was still unclear. The purpose of the current study was to evaluate the mechanism of Fas regulation by miR-20a in vitro and test the effect of targeting miR-20a in vivo. We investigated whether miR-20a's downregulation of Fas was mediated by binding to the 3' untranslated region (3'-UTR) of Fas mRNA with the consequent induction of mRNA degradation or translational suppression. We identified and mutated two miR-20a binding sites on the Fas mRNA 3'-UTR. Using luciferase reporter assays, we demonstrated that miR-20a did not bind to either the wild-type or mutated Fas 3'-UTR. By contrast, overexpression of miR-20a resulted in downregulation of Fas promoter activity. Similarly, the inhibition of miR-20a increased Fas promoter activity. The critical region identified on the Fas promoter was between -240 bp and 150 bp. Delivery of anti-miR-20a in vivo using nanoparticles in mice with established osteosarcoma lung metastases resulted in upregulation of Fas and tumor growth inhibition. Taken together, our data suggest that miR-20a regulates Fas expression through the modulation of the Fas promoter and that targeting miR-20a using anti-miR-20a has therapeutic potential.
http://ift.tt/2zeVoQN
HIF2{alpha} targeted RNAi therapeutic inhibits clear cell renal cell carcinoma
Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2α (HIF2α) and that an over-abundance of HIF2α functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2α that utilizes a targeting ligand that selectively binds to integrins αvβ3 and αvβ5 frequently over-expressed in ccRCC. We demonstrate that functional delivery of a HIF2α specific RNAi trigger resulted in HIF2α gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model.
http://ift.tt/2iFFyrd
RNA-Based Genetic Circuits Are a Potential Antitumor Immunotherapy [Research Watch]
Expression of synthetic RNA-based gene circuits in tumors induces an antitumor T-cell response.
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Trastuzumab Deruxtecan Is Safe and Active in HER2-Expressing Tumors [Research Watch]
Trastuzumab deruxtecan achieved responses in patients with breast, gastric, and gastroesophageal tumors.
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Adrenergic Nerves May Promote Angiogenesis in Prostate Cancer [Research Watch]
Deleting Adrb2, encoding the β2-adrenergic receptor, in tumor endothelial cells suppresses angiogenesis.
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Identified Selective USP7 Inhibitors Compete with Ubiquitin Binding [Research Watch]
Specific USP7 inhibitors stabilized p53 and exhibited toxicity in tumor cells in vitro and in vivo.
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Cancer "Clock" Opens New Therapeutic Avenues [News in Brief]
A better understanding of circadian genes, the focus of the 2017 Medicine Nobel, could improve patient care.
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SLC38A9 Links mTORC1 Activity to Lysosomal Amino Acid Release [Research Watch]
SLC38A9 acts as a lysosomal arginine sensor to activate mTORC1 signaling and support tumor growth.
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Epidermal growth factor receptor mutation predicts favorable outcomes in non-small cell lung cancer patients with brain metastases treated with stereotactic radiosurgery
The impact of epidermal growth factor receptor (EGFR) mutations on radiotherapy for brain metastases (BM) is undetermined. We evaluated the effects of EGFR mutation status on responses and outcomes in non-small cell lung cancer (NSCLC) patients with BM, treated with upfront or salvage stereotactic radiosurgery (SRS).
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Nutritional counseling with or without systematic use of oral nutritional supplements in head and neck cancer patients undergoing radiotherapy
To evaluate the benefit of oral nutritional supplements (ONS) in addition to nutritional counseling in head and neck cancer (HNC) patients undergoing radiotherapy (RT).
http://ift.tt/2zUYFlj
"Asian Pac J Cancer Prev"[jour]; +42 new citations
42 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
"Asian Pac J Cancer Prev"[jour]
These pubmed results were generated on 2017/10/27
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
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Overexpression of COX7A2 is associated with a good prognosis in patients with glioma
Abstract
Cytochrome c oxidase subunit 7A2 (COX7A2) is a nuclear-encoded polypeptide involved in assembly and regulation of cytochrome c oxidase (COX). Changes in the respiratory chain as big complex are known to be associated with cancer, but little research has been performed to discover COX7A2 as a prognostic marker in glioma. In the present study, we investigated COX7A2 expression and its prognostic significance in glioma. Glioma surgical tissue samples were taken from 126 patients who had been followed up from 4 to 51 months. Immunohistochemistry were used to test COX7A2 expression in the 126 tumor samples. Eighty-six of 126 (68.3%) paraffin-embedded glioma biopsies showed high expression of COX7A2. Statistical analysis displayed that there was significant difference of COX7A2 expression level in patients categorized according to WHO classification. Kaplan–Meier survival analysis revealed that patients with higher COX7A2 expression had longer overall survival time and better prognosis. R2: microarray analysis based on Tumor Glioma French 284 database, Tumor Glioblastoma TCGA 540 database, and Tumor Glioma Kawaguchi 50 database testified that high expression of COX7A2 is associated with a good prognosis in patients with glioma. Multivariate analysis showed that COX7A2 high expression was an independent prognostic indicator for survival. Our results suggest that COX7A2 could be served as a valuable prognostic marker of glioma.
http://ift.tt/2zbyHgi
Overexpression of COX7A2 is associated with a good prognosis in patients with glioma
Abstract
Cytochrome c oxidase subunit 7A2 (COX7A2) is a nuclear-encoded polypeptide involved in assembly and regulation of cytochrome c oxidase (COX). Changes in the respiratory chain as big complex are known to be associated with cancer, but little research has been performed to discover COX7A2 as a prognostic marker in glioma. In the present study, we investigated COX7A2 expression and its prognostic significance in glioma. Glioma surgical tissue samples were taken from 126 patients who had been followed up from 4 to 51 months. Immunohistochemistry were used to test COX7A2 expression in the 126 tumor samples. Eighty-six of 126 (68.3%) paraffin-embedded glioma biopsies showed high expression of COX7A2. Statistical analysis displayed that there was significant difference of COX7A2 expression level in patients categorized according to WHO classification. Kaplan–Meier survival analysis revealed that patients with higher COX7A2 expression had longer overall survival time and better prognosis. R2: microarray analysis based on Tumor Glioma French 284 database, Tumor Glioblastoma TCGA 540 database, and Tumor Glioma Kawaguchi 50 database testified that high expression of COX7A2 is associated with a good prognosis in patients with glioma. Multivariate analysis showed that COX7A2 high expression was an independent prognostic indicator for survival. Our results suggest that COX7A2 could be served as a valuable prognostic marker of glioma.
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[HBV infection: Screening and treatment for oncology patients].
| Related Articles |
[HBV infection: Screening and treatment for oncology patients].
Bull Cancer. 2017 Oct 21;:
Authors: Jaillais A, Herber-Mayne A, D'Alteroche L, Landau A, Merrouche Y, Vignot S
Abstract
Patients with chronic hepatitis B infection are at risk of viral reactivation when treated by immuno- or chemotherapy, with potentially serious or even fatal consequences. This article proposes an overview on screening strategies and antiviral treatment recommendations for oncology patients. We have learned in hematology that reactivations are commun with rituximab and prophylactic treatment is recommanded for any patient who has been in contact with the virus. The risk appears to be lower with cytotoxics but has been far less studied. The recommandations are not formally consensual and upcoming studies will help to establish clearer practice guidelines.
PMID: 29066086 [PubMed - as supplied by publisher]
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Anticancer Activity and Molecular Mechanism of Polyphenol Rich Calophyllum inophyllum Fruit Extract in MCF-7 Breast Cancer Cells.
| Related Articles |
Anticancer Activity and Molecular Mechanism of Polyphenol Rich Calophyllum inophyllum Fruit Extract in MCF-7 Breast Cancer Cells.
Nutr Cancer. 2017 Oct 25;:1-17
Authors: Shanmugapriya, Chen Y, Kanwar JR, Sasidharan S
Abstract
This study was conducted to investigate the anticancer effects and mechanism of Calophyllum inophyllum fruit extract against MCF-7 cells. C. inophyllum fruit extract was found to have markedly cytotoxic effect against MCF-7 cells in a dose-dependent manner with the IC50 for 24 h of 23.59 µg/mL. Flow cytometry analysis revealed that C. inophyllum fruit extract mediated cell cycle at G0/G1 and G2/M phases, and MCF-7 cells entered the early phase of apoptosis. The expression of anti-apoptotic proteins Bcl-2 was decreased whereas the expression of the pro-apoptotic protein Bax, cytochrome C and p53 were increased after treatment. C. inophyllum fruit extract led to apoptosis in MCF-7 cells via the mitochondrial pathway in a dose dependent manner. This is evidenced by the elevation of intracellular ROS, the loss of mitochondria membrane potential (Δψm), and activation of caspase-3. Meanwhile, dose-dependent genomic DNA fragmentation was observed after C. inophyllum fruits extract treatment by comet assay. This study shows that C. inophyllum fruits extract-induced apoptosis is primarily p53 dependent and mediated through the activation of caspase-3. C. inophyllum fruit extract could be an excellent source of chemopreventive agent in the treatment of breast cancer and has potential to be explored as green anticancer agent.
PMID: 29068745 [PubMed - as supplied by publisher]
http://ift.tt/2llun83
Silibinin Reduces the Impact of Obesity on Invasive Liver Cancer.
| Related Articles |
Silibinin Reduces the Impact of Obesity on Invasive Liver Cancer.
Nutr Cancer. 2017 Oct 25;:1-9
Authors: Miethe C, Nix H, Martin R, Hernandez AR, Price RS
Abstract
Obesity is associated with non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Obesity and metabolic abnormalities resulting in low-grade inflammation can increase the risk of developing NASH and HCC. NASH, a risk factor for HCC, is characterized by increased inflammation, lipid accumulation, and liver injury. Obesogenic proteins modulate signaling pathways that induce physiological changes including lipogenesis, ROS, and inflammation. Silibinin, a polyphenol in milk thistle seed, has been shown to have anti-inflammatory properties. Studies have yet to determine whether silibinin can be used to dissect the obesity-cancer link to delay progression of liver cancer. Using an in vitro model, sera from obese (OB), overweight (OW), or normal weight (NW) males (based on BMI) were used to determine the efficacy of silibinin to reduce the pro-tumorigenic properties of obesity. HepG2 cells were exposed to OB, OW, NW ± silibinin and tested for growth, ROS, lipogenesis, MMP-9, invasion and protein expression. Silibinin suppressed obesity-induced growth, ROS, lipogenesis, MMP-9, and cell invasion. These physiological changes corresponded with decreased FASN, IL-6, IL-1B, and phosphorylated Erk. We describe the differential effect of sera from OB, OW, and NW males on characteristics relevant for liver cancer and the potential use of silibinin to mitigate these effects.
PMID: 29068700 [PubMed - as supplied by publisher]
http://ift.tt/2lmvlAW
The Impact of Dietary Polyphenols on COX-2 Expression in Colorectal Cancer.
| Related Articles |
The Impact of Dietary Polyphenols on COX-2 Expression in Colorectal Cancer.
Nutr Cancer. 2017 Oct 25;:1-14
Authors: Owczarek K, Lewandowska U
Abstract
Polyphenols are natural compounds with high structural diversity whose common occurrence in plants renders them intrinsic dietary components. They are known to be secondary metabolites characterized by a wide spectrum of biological activities, and a growing body of evidence indicates they have anti-inflammatory potential. It is well known that inflammation plays a key role in many chronic diseases such as circulatory diseases, pulmonary diseases, autoimmune diseases, diabetes, cancer, and neurodegenerative diseases. Polyphenols influence the inflammatory process by controlling and inhibiting pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α, and cyclooxygenase-2 (COX-2) enzyme involved in the metabolism of arachidonic acid. Furthermore, polyphenols exhibit anti-inflammatory activity on many levels via NF-κB inhibition, and MAPK, iNOS, and growth factors regulation. This paper reviews the current state of knowledge concerning the potential of various dietary polyphenols to inhibit the effects of COX-2 in colon cancer, by examining the available evidence regarding the efficacy and safety of these compounds obtained from in vitro and animal studies.
PMID: 29068698 [PubMed - as supplied by publisher]
http://ift.tt/2lnkaYz
Overexpression of COX7A2 is associated with a good prognosis in patients with glioma
Abstract
Cytochrome c oxidase subunit 7A2 (COX7A2) is a nuclear-encoded polypeptide involved in assembly and regulation of cytochrome c oxidase (COX). Changes in the respiratory chain as big complex are known to be associated with cancer, but little research has been performed to discover COX7A2 as a prognostic marker in glioma. In the present study, we investigated COX7A2 expression and its prognostic significance in glioma. Glioma surgical tissue samples were taken from 126 patients who had been followed up from 4 to 51 months. Immunohistochemistry were used to test COX7A2 expression in the 126 tumor samples. Eighty-six of 126 (68.3%) paraffin-embedded glioma biopsies showed high expression of COX7A2. Statistical analysis displayed that there was significant difference of COX7A2 expression level in patients categorized according to WHO classification. Kaplan–Meier survival analysis revealed that patients with higher COX7A2 expression had longer overall survival time and better prognosis. R2: microarray analysis based on Tumor Glioma French 284 database, Tumor Glioblastoma TCGA 540 database, and Tumor Glioma Kawaguchi 50 database testified that high expression of COX7A2 is associated with a good prognosis in patients with glioma. Multivariate analysis showed that COX7A2 high expression was an independent prognostic indicator for survival. Our results suggest that COX7A2 could be served as a valuable prognostic marker of glioma.
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Anticancer Activity and Molecular Mechanism of Polyphenol Rich Calophyllum inophyllum Fruit Extract in MCF-7 Breast Cancer Cells.
| Related Articles |
Anticancer Activity and Molecular Mechanism of Polyphenol Rich Calophyllum inophyllum Fruit Extract in MCF-7 Breast Cancer Cells.
Nutr Cancer. 2017 Oct 25;:1-17
Authors: Shanmugapriya, Chen Y, Kanwar JR, Sasidharan S
Abstract
This study was conducted to investigate the anticancer effects and mechanism of Calophyllum inophyllum fruit extract against MCF-7 cells. C. inophyllum fruit extract was found to have markedly cytotoxic effect against MCF-7 cells in a dose-dependent manner with the IC50 for 24 h of 23.59 µg/mL. Flow cytometry analysis revealed that C. inophyllum fruit extract mediated cell cycle at G0/G1 and G2/M phases, and MCF-7 cells entered the early phase of apoptosis. The expression of anti-apoptotic proteins Bcl-2 was decreased whereas the expression of the pro-apoptotic protein Bax, cytochrome C and p53 were increased after treatment. C. inophyllum fruit extract led to apoptosis in MCF-7 cells via the mitochondrial pathway in a dose dependent manner. This is evidenced by the elevation of intracellular ROS, the loss of mitochondria membrane potential (Δψm), and activation of caspase-3. Meanwhile, dose-dependent genomic DNA fragmentation was observed after C. inophyllum fruits extract treatment by comet assay. This study shows that C. inophyllum fruits extract-induced apoptosis is primarily p53 dependent and mediated through the activation of caspase-3. C. inophyllum fruit extract could be an excellent source of chemopreventive agent in the treatment of breast cancer and has potential to be explored as green anticancer agent.
PMID: 29068745 [PubMed - as supplied by publisher]
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Silibinin Reduces the Impact of Obesity on Invasive Liver Cancer.
| Related Articles |
Silibinin Reduces the Impact of Obesity on Invasive Liver Cancer.
Nutr Cancer. 2017 Oct 25;:1-9
Authors: Miethe C, Nix H, Martin R, Hernandez AR, Price RS
Abstract
Obesity is associated with non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Obesity and metabolic abnormalities resulting in low-grade inflammation can increase the risk of developing NASH and HCC. NASH, a risk factor for HCC, is characterized by increased inflammation, lipid accumulation, and liver injury. Obesogenic proteins modulate signaling pathways that induce physiological changes including lipogenesis, ROS, and inflammation. Silibinin, a polyphenol in milk thistle seed, has been shown to have anti-inflammatory properties. Studies have yet to determine whether silibinin can be used to dissect the obesity-cancer link to delay progression of liver cancer. Using an in vitro model, sera from obese (OB), overweight (OW), or normal weight (NW) males (based on BMI) were used to determine the efficacy of silibinin to reduce the pro-tumorigenic properties of obesity. HepG2 cells were exposed to OB, OW, NW ± silibinin and tested for growth, ROS, lipogenesis, MMP-9, invasion and protein expression. Silibinin suppressed obesity-induced growth, ROS, lipogenesis, MMP-9, and cell invasion. These physiological changes corresponded with decreased FASN, IL-6, IL-1B, and phosphorylated Erk. We describe the differential effect of sera from OB, OW, and NW males on characteristics relevant for liver cancer and the potential use of silibinin to mitigate these effects.
PMID: 29068700 [PubMed - as supplied by publisher]
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The Impact of Dietary Polyphenols on COX-2 Expression in Colorectal Cancer.
| Related Articles |
The Impact of Dietary Polyphenols on COX-2 Expression in Colorectal Cancer.
Nutr Cancer. 2017 Oct 25;:1-14
Authors: Owczarek K, Lewandowska U
Abstract
Polyphenols are natural compounds with high structural diversity whose common occurrence in plants renders them intrinsic dietary components. They are known to be secondary metabolites characterized by a wide spectrum of biological activities, and a growing body of evidence indicates they have anti-inflammatory potential. It is well known that inflammation plays a key role in many chronic diseases such as circulatory diseases, pulmonary diseases, autoimmune diseases, diabetes, cancer, and neurodegenerative diseases. Polyphenols influence the inflammatory process by controlling and inhibiting pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α, and cyclooxygenase-2 (COX-2) enzyme involved in the metabolism of arachidonic acid. Furthermore, polyphenols exhibit anti-inflammatory activity on many levels via NF-κB inhibition, and MAPK, iNOS, and growth factors regulation. This paper reviews the current state of knowledge concerning the potential of various dietary polyphenols to inhibit the effects of COX-2 in colon cancer, by examining the available evidence regarding the efficacy and safety of these compounds obtained from in vitro and animal studies.
PMID: 29068698 [PubMed - as supplied by publisher]
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Propranolol in the preoperative treatment of Kasabach–Merritt syndrome: a case report
Kasabach–Merritt syndrome represents the association of hemangioma with thrombocytopenia and consumptive coagulopathy. We present a case of Kasabach–Merritt syndrome treatment with orally administered proprano...
http://ift.tt/2yPY2f8
Tumoral calcinosis in the cervical spine: a case report and review of the literature
Tumoral calcinosis is rarely located in spine. A 55-year-old Japanese woman with cervical tumoral calcinosis is presented, along with a review of the literature relating to tumoral calcinosis in the spine. We ...
http://ift.tt/2gP3cAX
Dual inhibition of the mTORC1 and mTORC2 signaling pathways is a promising therapeutic target for Adult T-cell Leukemia
Summary
ATL has a poor prognosis due to severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Recent integrated-genome analysis has revealed mutations in many genes involved in the T-cell signaling pathway, suggesting that the aberration of this pathway is an important factor in ATL pathogenesis and ATL-cell proliferation. We screened a siRNA library to examine signaling-pathway functionality and found that the PI3K/Akt/mTOR pathway is critical to ATL-cell proliferation. We therefore investigated the effect of mTOR inhibitors, including the dual inhibitors PP242 and AZD8055 and the mTORC1 inhibitors rapamycin and everolimus, on HTLV-1-infected-cell and ATL-cell lines. Both dual inhibitors inhibited the proliferation of all tested cell lines by inducing G1-phase cell-cycle arrest and subsequent cell apoptosis, whereas the effects of the two mTORC1 inhibitors were limited, as they did not induce cell apoptosis. In the ATL-cell lines and in the primary ATL samples, both dual inhibitors inhibited phosphorylation of AKT at serine-473, a target of mTORC2, as well as that of S6K, whereas the mTORC1 inhibitors only inhibited mTORC1. Furthermore, AZD8055 more significantly inhibited the in vivo growth of the ATL-cell xenografts than did everolimus. These results indicate that the PI3K/mTOR pathway is critical to ATL-cell proliferation and might thus be a new therapeutic target in ATL.
This article is protected by copyright. All rights reserved.
http://ift.tt/2gOZGXt
Dual inhibition of the mTORC1 and mTORC2 signaling pathways is a promising therapeutic target for Adult T-cell Leukemia
Summary
ATL has a poor prognosis due to severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Recent integrated-genome analysis has revealed mutations in many genes involved in the T-cell signaling pathway, suggesting that the aberration of this pathway is an important factor in ATL pathogenesis and ATL-cell proliferation. We screened a siRNA library to examine signaling-pathway functionality and found that the PI3K/Akt/mTOR pathway is critical to ATL-cell proliferation. We therefore investigated the effect of mTOR inhibitors, including the dual inhibitors PP242 and AZD8055 and the mTORC1 inhibitors rapamycin and everolimus, on HTLV-1-infected-cell and ATL-cell lines. Both dual inhibitors inhibited the proliferation of all tested cell lines by inducing G1-phase cell-cycle arrest and subsequent cell apoptosis, whereas the effects of the two mTORC1 inhibitors were limited, as they did not induce cell apoptosis. In the ATL-cell lines and in the primary ATL samples, both dual inhibitors inhibited phosphorylation of AKT at serine-473, a target of mTORC2, as well as that of S6K, whereas the mTORC1 inhibitors only inhibited mTORC1. Furthermore, AZD8055 more significantly inhibited the in vivo growth of the ATL-cell xenografts than did everolimus. These results indicate that the PI3K/mTOR pathway is critical to ATL-cell proliferation and might thus be a new therapeutic target in ATL.
This article is protected by copyright. All rights reserved.
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Correction to: Automated IMRT planning in Pinnacle—A study in head-and-neck cancer
Correction to:
Strahlenther Onkol 2017
http://ift.tt/2zIOwqS
Unfortunately, parts of the 'Materials and Methods section' and a sentence in the 'Discussion section' had to be corrected.
On page 3, left column, the complete first paragraph was corrected and now reads as follows:
Auto-P
http://ift.tt/2yQxoAc
Perceived cognitive impairment in people with colorectal cancer who do and do not receive chemotherapy
Abstract
Purpose
Cognitive symptoms are common after cancer, but poorly associated with neuropsychological results. We previously reported colorectal cancer (CRC) patients had more cognitive impairment than controls. Here, we explore relationships between cognitive symptoms and neuropsychological domains.
Methods
Subjects with CRC (N = 362) and 72 healthy controls completed neuropsychological assessments and Functional Assessment of Cancer Therapy-Cognition (FACT-COG) at baseline (pre-chemotherapy) and 6, 12, and 24 months. Associations between neuropsychological and FACT-COG scores were explored: perceived cognitive impairment (PCI), perceived cognitive ability (PCA), impact of PCI on quality of life (CogQOL).
Results
Of 362 CRC subjects, 289 had loco-regional disease and 173 received chemotherapy (CTh+). At baseline, groups did not differ on total FACT-COG, PCI, or PCA scores. All scores, except PCA, were worse at 6 months in CTh+. CRC patients not receiving chemotherapy did not differ from controls on FACT-COG domains. PCA associated weakly (r = 0.28–0.34) with attention/executive function, visual memory, and global deficit score. There was no association between PCI and neuropsychological domains. Fatigue, anxiety/depression, and poorer quality of life were associated with PCI and CogQOL (r = 0.44–0.51) in CRC patients.
Conclusions
No association was seen between total FACT-COG or PCI, and neuropsychological domains. A weak-moderate association was found between PCA and attention/executive function and visual memory.
Trial registration
The study was registered with clinicaltrials.gov (trial registration: NCT00188331).
Implications for cancer survivors
Cognitive symptoms are associated with fatigue, anxiety/depression, and poorer quality of life, and do not appear to be related to actual cognitive performance. Rates were lower than that reported in breast cancer survivors. Cognitive symptoms were greatest in those who received chemotherapy, with no significant difference between the non-chemotherapy survivors and healthy controls.
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No impact of perioperative blood transfusion on prognosis after curative resection for hepatocellular carcinoma: a propensity score matching analysis
Abstract
Background
The relationship between perioperative blood transfusion and long-term survival after curative resection for hepatocellular carcinoma (HCC) remains controversial. The aim of the present study was to investigate the impact of blood transfusion on the long-term prognosis of HCC patients.
Methods
Patients with primary HCC who underwent a curative hepatectomy from 2003 to 2011 were enrolled and then retrospectively studied. The clinicopathologic characteristics between patients in the blood transfusion and non-transfusion groups were matched using a propensity score matching (PSM) analysis. Univariate and multivariate Cox regression analyses were used to identify whether perioperative blood transfusion affects long-term survival after resection for HCC.
Results
A total of 374 patients were enrolled and 113 patients received perioperative transfusions. The 1-, 3- and 5-year disease-free and overall survival rates of the entire cohort were 65.0, 37.3 and 23.9%, and 90.9, 70.7 and 57.5%, respectively. The disease-free and overall survival rates of the blood transfusion group were significantly worse than the disease-free and overall survival rates of the non-transfusion group in the entire cohort (p < 0.001, p < 0.001). However, the differences in the survival rates between the two groups were no longer significant after PSM (p = 0.067, p = 0.105). Multivariate Cox analyses showed that perioperative blood transfusion was not an independent predictor of disease-free and overall survival in the propensity-matched cohort (p = 0.154, p = 0.667).
Conclusions
The present study demonstrates that perioperative blood transfusion has no impact on disease-free and overall survival after curative resection for HCC.
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Correction to: Automated IMRT planning in Pinnacle—A study in head-and-neck cancer
Correction to:
Strahlenther Onkol 2017
http://ift.tt/2zIOwqS
Unfortunately, parts of the 'Materials and Methods section' and a sentence in the 'Discussion section' had to be corrected.
On page 3, left column, the complete first paragraph was corrected and now reads as follows:
Auto-P
http://ift.tt/2yQxoAc
Perceived cognitive impairment in people with colorectal cancer who do and do not receive chemotherapy
Abstract
Purpose
Cognitive symptoms are common after cancer, but poorly associated with neuropsychological results. We previously reported colorectal cancer (CRC) patients had more cognitive impairment than controls. Here, we explore relationships between cognitive symptoms and neuropsychological domains.
Methods
Subjects with CRC (N = 362) and 72 healthy controls completed neuropsychological assessments and Functional Assessment of Cancer Therapy-Cognition (FACT-COG) at baseline (pre-chemotherapy) and 6, 12, and 24 months. Associations between neuropsychological and FACT-COG scores were explored: perceived cognitive impairment (PCI), perceived cognitive ability (PCA), impact of PCI on quality of life (CogQOL).
Results
Of 362 CRC subjects, 289 had loco-regional disease and 173 received chemotherapy (CTh+). At baseline, groups did not differ on total FACT-COG, PCI, or PCA scores. All scores, except PCA, were worse at 6 months in CTh+. CRC patients not receiving chemotherapy did not differ from controls on FACT-COG domains. PCA associated weakly (r = 0.28–0.34) with attention/executive function, visual memory, and global deficit score. There was no association between PCI and neuropsychological domains. Fatigue, anxiety/depression, and poorer quality of life were associated with PCI and CogQOL (r = 0.44–0.51) in CRC patients.
Conclusions
No association was seen between total FACT-COG or PCI, and neuropsychological domains. A weak-moderate association was found between PCA and attention/executive function and visual memory.
Trial registration
The study was registered with clinicaltrials.gov (trial registration: NCT00188331).
Implications for cancer survivors
Cognitive symptoms are associated with fatigue, anxiety/depression, and poorer quality of life, and do not appear to be related to actual cognitive performance. Rates were lower than that reported in breast cancer survivors. Cognitive symptoms were greatest in those who received chemotherapy, with no significant difference between the non-chemotherapy survivors and healthy controls.
http://ift.tt/2heqAVC
No impact of perioperative blood transfusion on prognosis after curative resection for hepatocellular carcinoma: a propensity score matching analysis
Abstract
Background
The relationship between perioperative blood transfusion and long-term survival after curative resection for hepatocellular carcinoma (HCC) remains controversial. The aim of the present study was to investigate the impact of blood transfusion on the long-term prognosis of HCC patients.
Methods
Patients with primary HCC who underwent a curative hepatectomy from 2003 to 2011 were enrolled and then retrospectively studied. The clinicopathologic characteristics between patients in the blood transfusion and non-transfusion groups were matched using a propensity score matching (PSM) analysis. Univariate and multivariate Cox regression analyses were used to identify whether perioperative blood transfusion affects long-term survival after resection for HCC.
Results
A total of 374 patients were enrolled and 113 patients received perioperative transfusions. The 1-, 3- and 5-year disease-free and overall survival rates of the entire cohort were 65.0, 37.3 and 23.9%, and 90.9, 70.7 and 57.5%, respectively. The disease-free and overall survival rates of the blood transfusion group were significantly worse than the disease-free and overall survival rates of the non-transfusion group in the entire cohort (p < 0.001, p < 0.001). However, the differences in the survival rates between the two groups were no longer significant after PSM (p = 0.067, p = 0.105). Multivariate Cox analyses showed that perioperative blood transfusion was not an independent predictor of disease-free and overall survival in the propensity-matched cohort (p = 0.154, p = 0.667).
Conclusions
The present study demonstrates that perioperative blood transfusion has no impact on disease-free and overall survival after curative resection for HCC.
http://ift.tt/2gOagxJ
DNA Methylation Regulated microRNAs in Human Cervical Cancer
Abstract
Regulation of miRNA gene expression by DNA promoter methylation may represent a key mechanism to drive cervical cancer progression. In order to understand the impact of DNA promoter methylation on miRNAs at various stages of cervical carcinogenesis, we performed DNA methylation microarray on Normal Cervical Epithelium (NCE), Cervical Intraepithelial Neoplasia (CIN I - III) and Squamous Cell Carcinoma (SCC) tissues to identify differentially methylated miRNAs followed by validation by bisulfite sequencing. Further, expression of miRNAs was analyzed by qRT-PCR in clinical tissues and cervical cancer cell lines. Transcriptional activity was determined by luciferase assay. We identified a total of 69 hypermethylated and hypomethylated miRNA promoters encompassing 78 CpG islands in all except Y chromosome, among the three groups. The candidate DNA promoters of miR-424 were significantly hypermethylated and miR-200b and miR-34c were significantly hypomethylated in SCC compared to NCE (p<0.05). Expression of miR-424, miR-200b and miR-34c were inversely correlated with promoter DNA methylation in tissue samples. Treatment of cell lines with 5-aza-2'-deoxycytidine showed differential expression in all three miRNAs. We observed a decrease in miRNA promoter activity following in vitro SssI methylase treatment of miR-424, miR-200b and miR-34c. Luciferase assay demonstrated that miR-200b and miR-424 functionally interacts with 3'-UTR of HIPK3 and RBBP6 respectively and decreased their activity in presence of miR-200b and miR-424 mimics transfected in SiHa cells. Taken together, we have identified deregulation of miRNAs by aberrant DNA promoter methylation, leading to its transcriptional silencing during cervical carcinogenesis, which can be potential targets for diagnosis and therapy. This article is protected by copyright. All rights reserved
http://ift.tt/2gIPFra
Dual mTORC1/mTORC2 blocker as a possible therapy for tauopathy in cellular model
Abstract
Tauopathy comprises a group of disorders caused by abnormal aggregates of tau protein. In these disorders phosphorylated tau protein tends to accumulate inside neuronal cells (soma) instead of the normal axonal distribution of tau. A suggested therapeutic strategy for tauopathy is to induce autophagy to increase the ability to get rid of the unwanted tau aggregates. One of the key controllers of autophagy is mTOR. Blocking mTOR leads to stimulation of autophagy. Recently, unravelling molecular structure of mTOR showed that it is formed of two subunits: mTORC1/C2. So, blocking both subunits of mTOR seems more attractive as it will explore all abilities of mTOR molecule. In the present study, we report using pp242 which is a dual mTORC1/C2 blocker in cellular model of tauopathy using LUHMES cell line. Adding fenazaquin to LUHMES cells induced tauopathy in the form of increased phospho tau aggregates. Moreover, fenazaquin treated cells showed the characteristic somatic redistribution of tau. PP242 use in the present tauopathy model reversed the pathology significantly without observable cellular toxicity for the used dosage of 1000 nM. The present study suggests the possible use of pp242 as a dual mTOR blocker to treat tauopathy.
http://ift.tt/2xrU3l1
DNA Methylation Regulated microRNAs in Human Cervical Cancer
Abstract
Regulation of miRNA gene expression by DNA promoter methylation may represent a key mechanism to drive cervical cancer progression. In order to understand the impact of DNA promoter methylation on miRNAs at various stages of cervical carcinogenesis, we performed DNA methylation microarray on Normal Cervical Epithelium (NCE), Cervical Intraepithelial Neoplasia (CIN I - III) and Squamous Cell Carcinoma (SCC) tissues to identify differentially methylated miRNAs followed by validation by bisulfite sequencing. Further, expression of miRNAs was analyzed by qRT-PCR in clinical tissues and cervical cancer cell lines. Transcriptional activity was determined by luciferase assay. We identified a total of 69 hypermethylated and hypomethylated miRNA promoters encompassing 78 CpG islands in all except Y chromosome, among the three groups. The candidate DNA promoters of miR-424 were significantly hypermethylated and miR-200b and miR-34c were significantly hypomethylated in SCC compared to NCE (p<0.05). Expression of miR-424, miR-200b and miR-34c were inversely correlated with promoter DNA methylation in tissue samples. Treatment of cell lines with 5-aza-2'-deoxycytidine showed differential expression in all three miRNAs. We observed a decrease in miRNA promoter activity following in vitro SssI methylase treatment of miR-424, miR-200b and miR-34c. Luciferase assay demonstrated that miR-200b and miR-424 functionally interacts with 3'-UTR of HIPK3 and RBBP6 respectively and decreased their activity in presence of miR-200b and miR-424 mimics transfected in SiHa cells. Taken together, we have identified deregulation of miRNAs by aberrant DNA promoter methylation, leading to its transcriptional silencing during cervical carcinogenesis, which can be potential targets for diagnosis and therapy. This article is protected by copyright. All rights reserved
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Dual mTORC1/mTORC2 blocker as a possible therapy for tauopathy in cellular model
Abstract
Tauopathy comprises a group of disorders caused by abnormal aggregates of tau protein. In these disorders phosphorylated tau protein tends to accumulate inside neuronal cells (soma) instead of the normal axonal distribution of tau. A suggested therapeutic strategy for tauopathy is to induce autophagy to increase the ability to get rid of the unwanted tau aggregates. One of the key controllers of autophagy is mTOR. Blocking mTOR leads to stimulation of autophagy. Recently, unravelling molecular structure of mTOR showed that it is formed of two subunits: mTORC1/C2. So, blocking both subunits of mTOR seems more attractive as it will explore all abilities of mTOR molecule. In the present study, we report using pp242 which is a dual mTORC1/C2 blocker in cellular model of tauopathy using LUHMES cell line. Adding fenazaquin to LUHMES cells induced tauopathy in the form of increased phospho tau aggregates. Moreover, fenazaquin treated cells showed the characteristic somatic redistribution of tau. PP242 use in the present tauopathy model reversed the pathology significantly without observable cellular toxicity for the used dosage of 1000 nM. The present study suggests the possible use of pp242 as a dual mTOR blocker to treat tauopathy.
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Title page / Editorial Board
Source:Cancer Epidemiology, Volume 50, Part A
http://ift.tt/2yPoZ2y
Table of contents
Source:Cancer Epidemiology, Volume 50, Part A
http://ift.tt/2gNPO09
An epidemiologic perspective on the stem cell hypothesis in human carcinogenesis
Source:Cancer Epidemiology, Volume 50, Part A
Author(s): David Schottenfeld
BackgroundTomasetti and Vogelstein have hypothesized that the patterns of cancer incidence in various cells and tissues are highly correlated with the estimated lifetime number of stem cell divisions. The authors reviewed the risks in tissues of 17 types of cancer from the United States and 69 additional countries. Positive correlations were observed consistently between the tissue − specific cancer incidence and the estimated lifetime number of stem cell divisions. The authors concluded that approximately two-thirds of global cancer incidence may be attributed to random DNA replication errors.MethodsAn epidemiologic perspective is presented that may serve as a counterpoint in interpreting organ-specific cancer risks. The unifying nature of the Tomasetti/Vogelstein hypothesis must be viewed in the context of diverse and contrasting global trends and patterns of types and "causes" of cancers that are closely linked with economic development and cultural lifestyle practices. The presentation is organized by reviewing the global burden of cancer; concepts of causal inferences and counterfactual assumptions; multifactorial causes of hepatocellular carcinoma and a hierarchy of causes that varies internationally; tobacco carcinogenesis and the multiplex associations with 19 cancer sites and tissues; profile in contrasts in transit through the small and large intestine.Observations and conclusionsIt is readily recognized that DNA replication errors and number of stem cell divisions may vary in individuals and populations due to external environmental genotoxic chemicals and biologic agents, and internal hormonal and metabolic factors. There is a striking contrast in the risk of adenocarcinoma in the small intestine with that in the large intestine. Tomasetti and Vogelstein indicated that the cumulative number of divisions of stem cells over a lifetime in normal epithelial mucosal cells from colorectal cancer patients was 4 time greater than in the epithelial tissue from patients with adenocarcinoma of the small intestine. Their conclusion would suggest a "seed" and "soil" interaction rather than exclusively the independence of either component. Namely, that the contrasting physiological, biochemical, microbial and immunological features in the lumen and on the mucosal surface of the large intestine, in contrast to that in the small intestine, would foster molecular genetic and epigenetic events that are advantageous to neoplasia in the large intestine.
http://ift.tt/2yRDEKG
Screening with whole-body magnetic resonance imaging in pediatric subjects with Li–Fraumeni syndrome: A single institution pilot study
Abstract
Background
Li–Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the TP53 gene and a high risk of childhood-onset malignancies. Cancer surveillance is challenging in pediatric mutation carriers given the anatomic spectrum of malignancies and young age of onset. Whole-body magnetic resonance imaging (WB-MRI) may provide an acceptable method for early cancer detection.
Procedure
We conducted a prospective feasibility pilot study of pediatric subjects (age < 18 years) with LFS to determine return rates for annual WB-MRI scan. Secondary objectives included characterization of incident cancers (and how they were detected).
Results
Forty-five WB-MRI scans in 20 subjects were performed over 5 years; two patients enrolled without subsequently undergoing scans. Eighty-nine percent of participants scanned (95% confidence interval: 67–99%) returned for second examinations. Fifty-five percent of participants required general anesthesia, which was well tolerated in all cases. Six patients required dedicated follow-up imaging. One participant required biopsy of a detected brain lesion; pathology demonstrated reactive gliosis. Another participant, with prior choroid plexus carcinoma, had a new brain lesion detected on clinical follow-up MRI not seen on WB-MRI 6 months prior. All other participants remain well (median: 3 years, range: 0.08–4 years).
Conclusions
WB-MRI in pediatric subjects is a well-tolerated approach to cancer surveillance despite the need for general anesthesia in some patients. A large multicenter trial would determine true test characteristics and efficacy of this approach for early cancer detection in children at high cancer risk.
http://ift.tt/2gHzZV2
The duration of anthracycline infusion should be at least one hour in children with cancer: A clinical practice guideline
Abstract
We aimed to provide recommendations on the infusion duration of anthracycline chemotherapy agents in children with cancer. This study also serves as a practice example of the essential steps that need to be taken when using a previously published systematic review to develop a high-quality clinical practice guideline. Although evidence was scarce and included adult studies, the panel was able (using the Grading of Recommendations Assessment, Development and Evaluation evidence-to-decision framework) to recommend in favor of an anthracycline infusion duration of at least 1 hr (strong recommendation, very low to moderate quality of evidence). Recommending a precise optimal prolonged infusion duration was currently not possible.
http://ift.tt/2i97akJ
Gene therapy for hemophilia
Abstract
Individuals with the inherited bleeding disorder hemophilia have achieved tremendous advances in clinical outcomes through widespread implementation of prophylactic replacement with safe and efficacious factor VIII and IX. However, despite this therapeutic approach, bleeds still occur, some with serious consequence, joint disease has not been eradicated, and patients have not yet been liberated from the need for regular intravenous infusions. The shift from protein replacement to gene replacement is offering great hope to achieve durable levels of plasma factor activity levels high enough to remove the risk for recurrent joint bleeding. For the first time, clinical trial results are showing promise for "curative" correction of the bleeding phenotype.
http://ift.tt/2i9778x
Increased prescription rates of anxiolytics and hypnotics to survivors of cancer in childhood, adolescence, and young adulthood—A population-based study
Abstract
Background
Survivors of cancer diagnosed in childhood, adolescence, or young adulthood (CAYACS) risk psychological morbidities later in life. The study compares prescription rates of anxiolytics and hypnotics among survivors to rates in age- and gender-matched controls.
Procedures
The population-based cohort included 5,341 cancer survivors, diagnosed ≤25 years of age during 1965–2000. For each survivor, three age- and gender-matched controls were randomly selected from the general population. Data were identified from the Norwegian Cancer and Population registries and linked to the Norwegian Prescription Database. A Cox proportional hazard model was applied to estimate hazard ratios (HRs) of prescriptions during 2004–2012 to the survivors with controls as referents.
Results
Survivors had an increased risk of being prescribed anxiolytics with crude rates of 16.9/1,000 person years compared to 11.8/1,000 person years in controls (HR 1.41; 95% confidence interval [CI] 1.29–1.54). The relative risk was highest for survivors of neuroblastomas (HR 2.62; 95% CI 1.11–6.16), bone tumors (HR 2.00; 95% CI 1.26–3.18), and central nervous system tumors (HR 1.90; 95% CI 1.40–2.51). The risk of being prescribed hypnotics was increased with crude rates of 20.8/1,000 person years compared to 14.3/1,000 person years in controls (HR 1.44; 95% CI 1.32–1.56). The relative risk was highest for survivors of gastrointestinal tumors (HR 1.80; 95% CI 1.04–3.10), leukemias (HR 1.78; 95% CI 1.32–2.38), and soft tissue cancers (HR 1.70; 95% CI 1.09–2.64).
Conclusions
Certain groups of CAYACS have an increased risk for being prescribed anxiolytics or hypnotics compared to controls. Diagnostic reasons for prescriptions are unknown, but the results indicate an increased emotional burden among these groups of survivors.
http://ift.tt/2gIqzbK
Irinotecan for relapsed Wilms tumor in pediatric patients: SIOP experience and review of the literature—A report from the SIOP Renal Tumor Study Group
Abstract
While irinotecan has been studied in various pediatric solid tumors, its potential role in Wilms tumor (WT) is less clear. We evaluated response and outcome of irinotecan-containing regimens in relapsed WT and compared our results to the available literature. Among 14 evaluable patients, one complete response (CR) and two partial responses (PRs) were observed in patients with initial intermediate-risk (CR and PR) and blastemal-type histologies (PR). Two patients were alive at last follow-up showing no evidence of disease. Our results and the reviewed literature suggest some effectiveness of irinotecan in the setting of relapsed WT.
http://ift.tt/2i8XExV
Table of contents
Source:Cancer Epidemiology, Volume 50, Part A
from Cancer via ola Kala on Inoreader http://ift.tt/2gNPO09
via IFTTT
Title page / Editorial Board
Source:Cancer Epidemiology, Volume 50, Part A
from Cancer via ola Kala on Inoreader http://ift.tt/2yPoZ2y
via IFTTT
An epidemiologic perspective on the stem cell hypothesis in human carcinogenesis
Source:Cancer Epidemiology, Volume 50, Part A
Author(s): David Schottenfeld
BackgroundTomasetti and Vogelstein have hypothesized that the patterns of cancer incidence in various cells and tissues are highly correlated with the estimated lifetime number of stem cell divisions. The authors reviewed the risks in tissues of 17 types of cancer from the United States and 69 additional countries. Positive correlations were observed consistently between the tissue − specific cancer incidence and the estimated lifetime number of stem cell divisions. The authors concluded that approximately two-thirds of global cancer incidence may be attributed to random DNA replication errors.MethodsAn epidemiologic perspective is presented that may serve as a counterpoint in interpreting organ-specific cancer risks. The unifying nature of the Tomasetti/Vogelstein hypothesis must be viewed in the context of diverse and contrasting global trends and patterns of types and "causes" of cancers that are closely linked with economic development and cultural lifestyle practices. The presentation is organized by reviewing the global burden of cancer; concepts of causal inferences and counterfactual assumptions; multifactorial causes of hepatocellular carcinoma and a hierarchy of causes that varies internationally; tobacco carcinogenesis and the multiplex associations with 19 cancer sites and tissues; profile in contrasts in transit through the small and large intestine.Observations and conclusionsIt is readily recognized that DNA replication errors and number of stem cell divisions may vary in individuals and populations due to external environmental genotoxic chemicals and biologic agents, and internal hormonal and metabolic factors. There is a striking contrast in the risk of adenocarcinoma in the small intestine with that in the large intestine. Tomasetti and Vogelstein indicated that the cumulative number of divisions of stem cells over a lifetime in normal epithelial mucosal cells from colorectal cancer patients was 4 time greater than in the epithelial tissue from patients with adenocarcinoma of the small intestine. Their conclusion would suggest a "seed" and "soil" interaction rather than exclusively the independence of either component. Namely, that the contrasting physiological, biochemical, microbial and immunological features in the lumen and on the mucosal surface of the large intestine, in contrast to that in the small intestine, would foster molecular genetic and epigenetic events that are advantageous to neoplasia in the large intestine.
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via IFTTT
Screening with whole-body magnetic resonance imaging in pediatric subjects with Li–Fraumeni syndrome: A single institution pilot study
Abstract
Background
Li–Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the TP53 gene and a high risk of childhood-onset malignancies. Cancer surveillance is challenging in pediatric mutation carriers given the anatomic spectrum of malignancies and young age of onset. Whole-body magnetic resonance imaging (WB-MRI) may provide an acceptable method for early cancer detection.
Procedure
We conducted a prospective feasibility pilot study of pediatric subjects (age < 18 years) with LFS to determine return rates for annual WB-MRI scan. Secondary objectives included characterization of incident cancers (and how they were detected).
Results
Forty-five WB-MRI scans in 20 subjects were performed over 5 years; two patients enrolled without subsequently undergoing scans. Eighty-nine percent of participants scanned (95% confidence interval: 67–99%) returned for second examinations. Fifty-five percent of participants required general anesthesia, which was well tolerated in all cases. Six patients required dedicated follow-up imaging. One participant required biopsy of a detected brain lesion; pathology demonstrated reactive gliosis. Another participant, with prior choroid plexus carcinoma, had a new brain lesion detected on clinical follow-up MRI not seen on WB-MRI 6 months prior. All other participants remain well (median: 3 years, range: 0.08–4 years).
Conclusions
WB-MRI in pediatric subjects is a well-tolerated approach to cancer surveillance despite the need for general anesthesia in some patients. A large multicenter trial would determine true test characteristics and efficacy of this approach for early cancer detection in children at high cancer risk.
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The duration of anthracycline infusion should be at least one hour in children with cancer: A clinical practice guideline
Abstract
We aimed to provide recommendations on the infusion duration of anthracycline chemotherapy agents in children with cancer. This study also serves as a practice example of the essential steps that need to be taken when using a previously published systematic review to develop a high-quality clinical practice guideline. Although evidence was scarce and included adult studies, the panel was able (using the Grading of Recommendations Assessment, Development and Evaluation evidence-to-decision framework) to recommend in favor of an anthracycline infusion duration of at least 1 hr (strong recommendation, very low to moderate quality of evidence). Recommending a precise optimal prolonged infusion duration was currently not possible.
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Gene therapy for hemophilia
Abstract
Individuals with the inherited bleeding disorder hemophilia have achieved tremendous advances in clinical outcomes through widespread implementation of prophylactic replacement with safe and efficacious factor VIII and IX. However, despite this therapeutic approach, bleeds still occur, some with serious consequence, joint disease has not been eradicated, and patients have not yet been liberated from the need for regular intravenous infusions. The shift from protein replacement to gene replacement is offering great hope to achieve durable levels of plasma factor activity levels high enough to remove the risk for recurrent joint bleeding. For the first time, clinical trial results are showing promise for "curative" correction of the bleeding phenotype.
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Increased prescription rates of anxiolytics and hypnotics to survivors of cancer in childhood, adolescence, and young adulthood—A population-based study
Abstract
Background
Survivors of cancer diagnosed in childhood, adolescence, or young adulthood (CAYACS) risk psychological morbidities later in life. The study compares prescription rates of anxiolytics and hypnotics among survivors to rates in age- and gender-matched controls.
Procedures
The population-based cohort included 5,341 cancer survivors, diagnosed ≤25 years of age during 1965–2000. For each survivor, three age- and gender-matched controls were randomly selected from the general population. Data were identified from the Norwegian Cancer and Population registries and linked to the Norwegian Prescription Database. A Cox proportional hazard model was applied to estimate hazard ratios (HRs) of prescriptions during 2004–2012 to the survivors with controls as referents.
Results
Survivors had an increased risk of being prescribed anxiolytics with crude rates of 16.9/1,000 person years compared to 11.8/1,000 person years in controls (HR 1.41; 95% confidence interval [CI] 1.29–1.54). The relative risk was highest for survivors of neuroblastomas (HR 2.62; 95% CI 1.11–6.16), bone tumors (HR 2.00; 95% CI 1.26–3.18), and central nervous system tumors (HR 1.90; 95% CI 1.40–2.51). The risk of being prescribed hypnotics was increased with crude rates of 20.8/1,000 person years compared to 14.3/1,000 person years in controls (HR 1.44; 95% CI 1.32–1.56). The relative risk was highest for survivors of gastrointestinal tumors (HR 1.80; 95% CI 1.04–3.10), leukemias (HR 1.78; 95% CI 1.32–2.38), and soft tissue cancers (HR 1.70; 95% CI 1.09–2.64).
Conclusions
Certain groups of CAYACS have an increased risk for being prescribed anxiolytics or hypnotics compared to controls. Diagnostic reasons for prescriptions are unknown, but the results indicate an increased emotional burden among these groups of survivors.
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Irinotecan for relapsed Wilms tumor in pediatric patients: SIOP experience and review of the literature—A report from the SIOP Renal Tumor Study Group
Abstract
While irinotecan has been studied in various pediatric solid tumors, its potential role in Wilms tumor (WT) is less clear. We evaluated response and outcome of irinotecan-containing regimens in relapsed WT and compared our results to the available literature. Among 14 evaluable patients, one complete response (CR) and two partial responses (PRs) were observed in patients with initial intermediate-risk (CR and PR) and blastemal-type histologies (PR). Two patients were alive at last follow-up showing no evidence of disease. Our results and the reviewed literature suggest some effectiveness of irinotecan in the setting of relapsed WT.
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Oxygen-15 labeled CO 2 , O 2 , and CO PET in small animals: evaluation using a 3D-mode microPET scanner and impact of reconstruction algorithms
Abstract
Background
Positron emission tomography (PET) studies using 15O-labeled CO2, O2, and CO have been used in humans to evaluate cerebral blood flow (CBF), the cerebral oxygen extraction fraction (OEF), and the cerebral metabolic rate of oxygen (CMRO2) and cerebral blood volume (CBV), respectively. In preclinical studies, however, PET studies using 15O-labeled gases are not widely performed because of the technical difficulties associated with handling labeled gases with a short half-life. The aims of the present study were to evaluate the scatter fraction using 3D-mode micro-PET for 15O-labeled gas studies and the influence of reconstruction algorithms on quantitative values.
Nine male SD rats were studied using the steady state inhalation method for 15O-labeled gases with arterial blood sampling. The resulting PET images were reconstructed using filtered back projection (FBP), ordered-subset expectation maximization (OSEM) 2D, or OSEM 3D followed by maximum a posteriori (OSEM3D-MAP). The quantitative values for each brain region and each reconstruction method were calculated by applying different reconstruction methods.
Results
The quantitative values for the whole brain as calculated using FBP were 46.6 ± 12.5 mL/100 mL/min (CBF), 63.7 ± 7.2% (OEF), 5.72 ± 0.34 mL/100 mL/min (CMRO2), and 5.66 ± 0.34 mL/100 mL (CBV), respectively. The CBF and CMRO2 values were significantly higher when the OSEM2D and OSEM3D-MAP reconstruction methods were used, compared with FBP, whereas the OEF values were significantly lower when reconstructed using OSEM3D-MAP.
Conclusions
We evaluated the difference in quantitative values among the reconstruction algorithms using 3D-mode micro-PET. The iterative reconstruction method resulted in significantly higher quantitative values for CBF and CMRO2, compared with the values calculated using the FBP reconstruction method.
http://ift.tt/2gGsyx6
Safety, pharmacokinetics, metabolism and radiation dosimetry of 18 F-tetrafluoroborate ( 18 F-TFB) in healthy human subjects
Abstract
Background
18F-Tetrafluoroborate (18F-TFB) is a promising iodide analog for PET imaging of thyroid cancer and sodium/iodide symporter (NIS) reporter activity in viral therapy applications. The aim of this study was to evaluate the safety, pharmacokinetics, biodistribution, and radiation dosimetry of high-specific activity 18F-TFB in healthy human subjects.
Methods
18F-TFB was synthesized with specific activity of 3.2 ± 1.3 GBq/μmol (at the end of synthesis). Dynamic and whole-body static PET/CT scans over 4 h were performed after intravenous administration of 18F-TFB (333–407 MBq) in four female and four male healthy volunteers (35 ± 11 years old). Samples of venous blood and urine were collected over the imaging period and analyzed by ion-chromatography HPLC to determine tracer stability. Vital signs and clinical laboratory safety assays were measured to evaluate safety.
Results
18F-TFB administration was well tolerated with no significant findings on vital signs and no clinically meaningful changes in clinical laboratory assays. Left-ventricular blood pool time-activity curves showed a multi-phasic blood clearance of 18F-radioactivity with the two rapid clearance phases over the first 20 min, followed by a slower clearance phase. HPLC analysis showed insignificant 18F-labeled metabolites in the blood and urine over the length of the study (4 h). High uptakes were seen in the thyroid, stomach, salivary glands, and bladder. Urinary clearance of 18F-TFB was prominent. Metabolic stability was evidenced by low accumulation of 18F-radioactivity in the bone. Effective doses were 0.036 mSv/MBq in males and 0.064 mSv/MBq in females (p = 0.08, not significant).
Conclusions
This initial study in healthy human subjects showed 18F-TFB was safe and distributed in the human body similar to other iodide analogs. These data support further translational studies with 18F-TFB as NIS gene reporter and imaging biomarker for thyroid cancer and other disease processes that import iodide.
http://ift.tt/2i8AVC5
Oxygen-15 labeled CO 2 , O 2 , and CO PET in small animals: evaluation using a 3D-mode microPET scanner and impact of reconstruction algorithms
Abstract
Background
Positron emission tomography (PET) studies using 15O-labeled CO2, O2, and CO have been used in humans to evaluate cerebral blood flow (CBF), the cerebral oxygen extraction fraction (OEF), and the cerebral metabolic rate of oxygen (CMRO2) and cerebral blood volume (CBV), respectively. In preclinical studies, however, PET studies using 15O-labeled gases are not widely performed because of the technical difficulties associated with handling labeled gases with a short half-life. The aims of the present study were to evaluate the scatter fraction using 3D-mode micro-PET for 15O-labeled gas studies and the influence of reconstruction algorithms on quantitative values.
Nine male SD rats were studied using the steady state inhalation method for 15O-labeled gases with arterial blood sampling. The resulting PET images were reconstructed using filtered back projection (FBP), ordered-subset expectation maximization (OSEM) 2D, or OSEM 3D followed by maximum a posteriori (OSEM3D-MAP). The quantitative values for each brain region and each reconstruction method were calculated by applying different reconstruction methods.
Results
The quantitative values for the whole brain as calculated using FBP were 46.6 ± 12.5 mL/100 mL/min (CBF), 63.7 ± 7.2% (OEF), 5.72 ± 0.34 mL/100 mL/min (CMRO2), and 5.66 ± 0.34 mL/100 mL (CBV), respectively. The CBF and CMRO2 values were significantly higher when the OSEM2D and OSEM3D-MAP reconstruction methods were used, compared with FBP, whereas the OEF values were significantly lower when reconstructed using OSEM3D-MAP.
Conclusions
We evaluated the difference in quantitative values among the reconstruction algorithms using 3D-mode micro-PET. The iterative reconstruction method resulted in significantly higher quantitative values for CBF and CMRO2, compared with the values calculated using the FBP reconstruction method.
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Safety, pharmacokinetics, metabolism and radiation dosimetry of 18 F-tetrafluoroborate ( 18 F-TFB) in healthy human subjects
Abstract
Background
18F-Tetrafluoroborate (18F-TFB) is a promising iodide analog for PET imaging of thyroid cancer and sodium/iodide symporter (NIS) reporter activity in viral therapy applications. The aim of this study was to evaluate the safety, pharmacokinetics, biodistribution, and radiation dosimetry of high-specific activity 18F-TFB in healthy human subjects.
Methods
18F-TFB was synthesized with specific activity of 3.2 ± 1.3 GBq/μmol (at the end of synthesis). Dynamic and whole-body static PET/CT scans over 4 h were performed after intravenous administration of 18F-TFB (333–407 MBq) in four female and four male healthy volunteers (35 ± 11 years old). Samples of venous blood and urine were collected over the imaging period and analyzed by ion-chromatography HPLC to determine tracer stability. Vital signs and clinical laboratory safety assays were measured to evaluate safety.
Results
18F-TFB administration was well tolerated with no significant findings on vital signs and no clinically meaningful changes in clinical laboratory assays. Left-ventricular blood pool time-activity curves showed a multi-phasic blood clearance of 18F-radioactivity with the two rapid clearance phases over the first 20 min, followed by a slower clearance phase. HPLC analysis showed insignificant 18F-labeled metabolites in the blood and urine over the length of the study (4 h). High uptakes were seen in the thyroid, stomach, salivary glands, and bladder. Urinary clearance of 18F-TFB was prominent. Metabolic stability was evidenced by low accumulation of 18F-radioactivity in the bone. Effective doses were 0.036 mSv/MBq in males and 0.064 mSv/MBq in females (p = 0.08, not significant).
Conclusions
This initial study in healthy human subjects showed 18F-TFB was safe and distributed in the human body similar to other iodide analogs. These data support further translational studies with 18F-TFB as NIS gene reporter and imaging biomarker for thyroid cancer and other disease processes that import iodide.
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Meta-analytic evaluation of the association between head injury and risk of amyotrophic lateral sclerosis
Abstract
Head injury is considered as a potential risk factor for amyotrophic lateral sclerosis (ALS). However, several recent studies have suggested that head injury is not a cause, but a consequence of latent ALS. We aimed to evaluate such a possibility of reverse causation with meta-analyses considering time lags between the incidence of head injuries and the occurrence of ALS. We searched Medline and Web of Science for case–control, cross-sectional, or cohort studies that quantitatively investigated the head-injury-related risk of ALS and were published until 1 December 2016. After selecting appropriate publications based on PRISMA statement, we performed random-effects meta-analyses to calculate odds ratios (ORs) and 95% confidence intervals (CI). Sixteen of 825 studies fulfilled the eligibility criteria. The association between head injuries and ALS was statistically significant when the meta-analysis included all the 16 studies (OR 1.45, 95% CI 1.21–1.74). However, in the meta-analyses considering the time lags between the experience of head injuries and diagnosis of ALS, the association was weaker (OR 1.21, 95% CI 1.01–1.46, time lag ≥ 1 year) or not significant (e.g. OR 1.16, 95% CI 0.84–1.59, time lag ≥ 3 years). Although it did not deny associations between head injuries and ALS, the current study suggests a possibility that such a head-injury-oriented risk of ALS has been somewhat overestimated. For more accurate evaluation, it would be necessary to conduct more epidemiological studies that consider the time lags between the occurrence of head injuries and the diagnosis of ALS.
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H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas
Publication date: Available online 26 October 2017
Source:Cancer Cell
Author(s): Manav Pathania, Nicolas De Jay, Nicola Maestro, Ashot S. Harutyunyan, Justyna Nitarska, Pirasteh Pahlavan, Stephen Henderson, Leonie G. Mikael, Angela Richard-Londt, Ying Zhang, Joana R. Costa, Steven Hébert, Sima Khazaei, Nisreen Samir Ibrahim, Javier Herrero, Antonella Riccio, Steffen Albrecht, Robin Ketteler, Sebastian Brandner, Claudia L. Kleinman, Nada Jabado, Paolo Salomoni
Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha (PDGFRA) amplification. Here, we describe a somatic mouse model wherein H3.3K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3K27M-driven lesions are clonal, H3K27me3 depleted, Olig2 positive, highly proliferative, and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown is associated with more circumscribed tumors. H3.3K27M-tumor cells serially engraft in recipient mice, and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3K27M-pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies.
Graphical abstract
Teaser
Pathania et al. create a model of pediatric high-grade glioma with H3.3K27M/Trp53 mutation. Tumors occur only when alterations are introduced during a specific window of mouse development, and levels of PDGFRA and ATRX modulate tumor phenotype. This model enables the identification of mutation-specific vulnerabilities.from Cancer via ola Kala on Inoreader http://ift.tt/2y86w1P
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No impact of perioperative blood transfusion on prognosis after curative resection for hepatocellular carcinoma: a propensity score matching analysis
Abstract
Background
The relationship between perioperative blood transfusion and long-term survival after curative resection for hepatocellular carcinoma (HCC) remains controversial. The aim of the present study was to investigate the impact of blood transfusion on the long-term prognosis of HCC patients.
Methods
Patients with primary HCC who underwent a curative hepatectomy from 2003 to 2011 were enrolled and then retrospectively studied. The clinicopathologic characteristics between patients in the blood transfusion and non-transfusion groups were matched using a propensity score matching (PSM) analysis. Univariate and multivariate Cox regression analyses were used to identify whether perioperative blood transfusion affects long-term survival after resection for HCC.
Results
A total of 374 patients were enrolled and 113 patients received perioperative transfusions. The 1-, 3- and 5-year disease-free and overall survival rates of the entire cohort were 65.0, 37.3 and 23.9%, and 90.9, 70.7 and 57.5%, respectively. The disease-free and overall survival rates of the blood transfusion group were significantly worse than the disease-free and overall survival rates of the non-transfusion group in the entire cohort (p < 0.001, p < 0.001). However, the differences in the survival rates between the two groups were no longer significant after PSM (p = 0.067, p = 0.105). Multivariate Cox analyses showed that perioperative blood transfusion was not an independent predictor of disease-free and overall survival in the propensity-matched cohort (p = 0.154, p = 0.667).
Conclusions
The present study demonstrates that perioperative blood transfusion has no impact on disease-free and overall survival after curative resection for HCC.
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H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas
Publication date: Available online 26 October 2017
Source:Cancer Cell
Author(s): Manav Pathania, Nicolas De Jay, Nicola Maestro, Ashot S. Harutyunyan, Justyna Nitarska, Pirasteh Pahlavan, Stephen Henderson, Leonie G. Mikael, Angela Richard-Londt, Ying Zhang, Joana R. Costa, Steven Hébert, Sima Khazaei, Nisreen Samir Ibrahim, Javier Herrero, Antonella Riccio, Steffen Albrecht, Robin Ketteler, Sebastian Brandner, Claudia L. Kleinman, Nada Jabado, Paolo Salomoni
Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha (PDGFRA) amplification. Here, we describe a somatic mouse model wherein H3.3K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3K27M-driven lesions are clonal, H3K27me3 depleted, Olig2 positive, highly proliferative, and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown is associated with more circumscribed tumors. H3.3K27M-tumor cells serially engraft in recipient mice, and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3K27M-pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies.
Graphical abstract
Teaser
Pathania et al. create a model of pediatric high-grade glioma with H3.3K27M/Trp53 mutation. Tumors occur only when alterations are introduced during a specific window of mouse development, and levels of PDGFRA and ATRX modulate tumor phenotype. This model enables the identification of mutation-specific vulnerabilities.http://ift.tt/2y86w1P
No impact of perioperative blood transfusion on prognosis after curative resection for hepatocellular carcinoma: a propensity score matching analysis
Abstract
Background
The relationship between perioperative blood transfusion and long-term survival after curative resection for hepatocellular carcinoma (HCC) remains controversial. The aim of the present study was to investigate the impact of blood transfusion on the long-term prognosis of HCC patients.
Methods
Patients with primary HCC who underwent a curative hepatectomy from 2003 to 2011 were enrolled and then retrospectively studied. The clinicopathologic characteristics between patients in the blood transfusion and non-transfusion groups were matched using a propensity score matching (PSM) analysis. Univariate and multivariate Cox regression analyses were used to identify whether perioperative blood transfusion affects long-term survival after resection for HCC.
Results
A total of 374 patients were enrolled and 113 patients received perioperative transfusions. The 1-, 3- and 5-year disease-free and overall survival rates of the entire cohort were 65.0, 37.3 and 23.9%, and 90.9, 70.7 and 57.5%, respectively. The disease-free and overall survival rates of the blood transfusion group were significantly worse than the disease-free and overall survival rates of the non-transfusion group in the entire cohort (p < 0.001, p < 0.001). However, the differences in the survival rates between the two groups were no longer significant after PSM (p = 0.067, p = 0.105). Multivariate Cox analyses showed that perioperative blood transfusion was not an independent predictor of disease-free and overall survival in the propensity-matched cohort (p = 0.154, p = 0.667).
Conclusions
The present study demonstrates that perioperative blood transfusion has no impact on disease-free and overall survival after curative resection for HCC.
http://ift.tt/2gOagxJ
No impact of perioperative blood transfusion on prognosis after curative resection for hepatocellular carcinoma: a propensity score matching analysis
Abstract
Background
The relationship between perioperative blood transfusion and long-term survival after curative resection for hepatocellular carcinoma (HCC) remains controversial. The aim of the present study was to investigate the impact of blood transfusion on the long-term prognosis of HCC patients.
Methods
Patients with primary HCC who underwent a curative hepatectomy from 2003 to 2011 were enrolled and then retrospectively studied. The clinicopathologic characteristics between patients in the blood transfusion and non-transfusion groups were matched using a propensity score matching (PSM) analysis. Univariate and multivariate Cox regression analyses were used to identify whether perioperative blood transfusion affects long-term survival after resection for HCC.
Results
A total of 374 patients were enrolled and 113 patients received perioperative transfusions. The 1-, 3- and 5-year disease-free and overall survival rates of the entire cohort were 65.0, 37.3 and 23.9%, and 90.9, 70.7 and 57.5%, respectively. The disease-free and overall survival rates of the blood transfusion group were significantly worse than the disease-free and overall survival rates of the non-transfusion group in the entire cohort (p < 0.001, p < 0.001). However, the differences in the survival rates between the two groups were no longer significant after PSM (p = 0.067, p = 0.105). Multivariate Cox analyses showed that perioperative blood transfusion was not an independent predictor of disease-free and overall survival in the propensity-matched cohort (p = 0.154, p = 0.667).
Conclusions
The present study demonstrates that perioperative blood transfusion has no impact on disease-free and overall survival after curative resection for HCC.
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