Comparative effectiveness between two types of head-mounted magnification modes using a smartphone-based virtual display.

SIGNIFICANCE: This work shows the benefits of using two different magnification strategies to improve the reading ability of low-vision patients using a head-mounted technology. PURPOSE: The aim of this study was to conduct a comparative clinical trial evaluating the effectiveness of two magnification strategies in a head-mounted virtual reality display. METHODS: Eighty-eight eligible low-vision subjects were randomized into two arms: (1) the full-field magnification display or (2) the virtual bioptic telescope mode. Subjects completed baseline testing and received training on how to use the device properly and then took the device home for a 2- to 4-week intervention period. An adaptive rating scale questionnaire (Activity Inventory) was administered before and after the intervention (home trial) period to measure the effect of the system. A Simulator Sickness Questionnaire was also administered. Baseline and follow-up results were analyzed using Rasch analysis to assess overall effectiveness of each magnification mode for various functional domain categories. RESULTS: Both magnification modes showed a positive effect for reading, visual information, and the overall goals functional domain categories, with only reading reaching statistical significance after correction for multiple comparisons. However, there were no significant between-group differences between the two modes. The results of the Simulator Sickness Questionnaire showed that the magnification modes of the head-mounted display device were overall well tolerated among low-vision users. CONCLUSIONS: Both the full-field and virtual bioptic magnification strategies were effective in significantly improving functional vision outcomes for self-reported reading ability.

NRP1 knockdown inhibits the invasion and migration of rhabdoid tumor of the kidney cells.

PURPOSE: The aim of this study was to detect candidate oncogenes of rhabdoid tumor of the kidney (RTK) and evaluate their roles in RTK in vitro. METHODS: An integrated analysis of messenger RNA (mRNA) and microRNA (miRNA) sequencing was performed to determine the expression profile of exosome-derived miRNAs and mRNAs in human RTK-derived cell lines and a human embryonic renal cell line. A Gene Ontology enrichment analysis was performed to analyze the functional characteristics of differentially expressed mRNAs in RTK cells. Matrigel invasion and wound-healing assays were performed to evaluate the cell invasion and migration abilities. RESULTS: Forty mRNAs were highly expressed in RTK cells targeted by exosomal miRNAs, the expression of which was lower in RTK cells than in the controls. These mRNAs were primarily related to cell adhesion. Of these mRNAs, we selected neuropilin 1 (NRP1) as a candidate oncogene because its upregulated expression is associated with a poor prognosis of several types of tumors. RTK cells in which NRP1 had been knocked down exhibited decreased invasive and migratory abilities. CONCLUSION: Our study indicates that NRP1 acts as an oncogene by promoting the invasion and migration of RTK cells and that it could serve as a therapeutic target.

Application of Rasch Analysis to Timed Instrumental Activities of Daily Living in Low Vision: A Validation Study.

SIGNIFICANCE: This work validates Rasch analysis of a performance-based low vision outcome measure evaluated in patients' own homes to ensure real-world relevance. Inclusion of sources of variance from the patient's home environment in functional outcome measures introduced nonuniform variance in measurements but did not preclude estimation of valid measures. PURPOSE: This study aimed to validate Rasch analysis of a performance-based outcome measure with real-world relevance. METHODS: Low vision patients (N = 161) receiving services from an occupational therapist performed Timed Instrumental Activity of Daily Living (TIADL) tasks in their homes. Rasch analysis was applied to error count and performance time data. Internal validity was assessed with evaluations of the accuracy and precision of estimated measures. External validity was assessed by comparing TIADL measures with measures estimated from the Activity Inventory (i.e., from self-reported difficulty ratings). RESULTS: Task measures were well targeted to person measures estimated from task performance time but were poorly targeted for measures estimated from task performance errors, for which most task trials (72%) were performed without error at baseline. Error-based person measures had larger standard errors with a smaller pseudo- R2 than time-based person or task measures and error-based task measures. Person measure infits for time- and error-based estimates conformed to expected values. The linear regressions between time-based person and task measures and corresponding error-based estimates had slopes of approximately 0.5, an observation consistent with larger estimation error variance for error-based measures than for time-based measures. Time-based TIADL person measures ( x ) and Activity Inventory person measures (estimated from all items, y ) were colinear but weakly correlated ( R = 0.19). CONCLUSIONS: Functional ability measures estimated from performance times of instrumental activity of daily living tasks in patients' homes demonstrate good internal and external validity. The ceiling effect from the infrequency of task performance errors in our data set limits use of TIADL error data to measure rehabilitation outcomes.

Antitumor effects of pyrrole-imidazole polyamide modified with alkylating agent on prostate cancer cells.

Androgens and androgen receptor (AR) have a central role in prostate cancer progression by regulating its downstream signaling. Although androgen depletion therapy (ADT) is the primary treatment for most prostate cancers, they acquires resistance to ADT and become castration resistant prostate cancers (CRPC). AR complex formation with multiple transcription factors is important for enhancer activity and transcriptional regulation, which can contribute to cancer progression and resistance to ADT. We previously demonstrated that OCT1 collaborates with AR in prostate cancer, and that a pyrrole-imidazole (PI) polyamide (PIP) targeting OCT1 inhibits cell and castration-resistant tumor growth (Obinata D et al. Oncogene 2016). PIP can bind to DNA non-covalently without a drug delivery system unlike most DNA targeted therapeutics. In the present study, we developed a PIP modified with a DNA alkylating agent, chlorambucil (ChB) (OCT1-PIP-ChB). Then its effect on the growth of prostate cancer LNCaP, 22Rv1, and PC3 cells, pancreatic cancer BxPC3 cells, and colon cancer HCT116 cells, as well as non-cancerous MCF-10A epithelial cells, were analyzed. It was shown that the IC50s of OCT1-PIP-ChB for 22Rv1 and LNCaP were markedly lower compared to other cells, including non-cancerous MCF-10A cells. Comprehensive gene expression analysis of CRPC model 22Rv1 cells treated with IC50 concentrations of OCT1-PIP-ChB revealed that the gene group involved in DNA double-strand break repair was the most enriched among gene sets repressed by OCT1-PIP-ChB treatment. Importantly, in vivo study using 22Rv1 xenografts, we showed that OCT1-PIP-ChB significantly reduced tumor growth compared to the control group without showing obvious adverse effects. Thus, the PIP combined with ChB can exert a significant inhibitory effect on prostate cancer cell proliferation and castration-resistant tumor growth, suggesting a potential role as a therapeutic agent.

Exosomal miR-214-3p as a potential novel biomarker for rhabdoid tumor of the kidney.

PURPOSE: Rhabdoid tumor of the kidney (RTK) is a rare, highly aggressive pediatric renal tumor. No specific biomarkers are available for detection of RTK, and the initial differential diagnosis from other pediatric abdominal tumors, including neuroblastoma (NB), is difficult. Exosomal miRNAs are novel cancer biomarkers that can be detected in biological fluids. We explored candidate RTK-specific exosomal miRNAs as novel biomarkers of RTK. METHODS: Exosomal miRNAs were collected from conditioned media of human RTK-derived cell lines, a human embryonic renal cell line, and human NB-derived cell lines. miRNA sequencing (miRNA-Seq) was performed to detect candidate RTK-specific exosomal miRNAs. The exosomal miRNA expression in conditioned media of tumor cell lines and serum from RTK xenograft-bearing mice was analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: The expression of exosomal miR-214-3p detected by miRNA-Seq was highest in RTK-derived cell lines. Exosomal miR-214-3p expression level determined by qRT-PCR was significantly higher in RTK-derived cell lines than in the human embryonic renal cell line or NB-derived cell lines. Furthermore, the serum exosomal miR-214-3p expression level was significantly higher in RTK xenograft mice than controls. CONCLUSION: Our data indicated that exosomal miR-214-3p has potential as a novel biomarker of RTK.

Polyethylene glycol derivative 9bw suppresses growth of neuroblastoma cells by inhibiting oxidative phosphorylation.

Neuroblastoma (NB) is a childhood malignancy originating from the sympathetic nervous system, and accounts for approximately 15% of all pediatric cancer-related deaths. As the 5-y survival rate of patients with high-risk NB is <50%, novel therapeutic strategies for NB patients are urgently required. Nonaethylene glycol mono('4-iodo-4-biphenyl)ester (9bw) is a polyethylene glycol derivative, synthesized by modifying a compound originally extracted from filamentous bacteria. Although 9bw shows remarkable inhibition of tumor cell growth, the underlying mechanisms remain unclear. Here, we examined the efficacy of 9bw on human NB-derived cells, and investigated the molecular mechanisms underlying the cytotoxic effects of 9bw on these cells. Our results indicated that 9bw induced cell death in NB cells by decreasing the production of ATP. Metabolome analysis and measurement of oxygen consumption indicated that 9bw markedly suppressed oxidative phosphorylation (OXPHOS). Further analyses indicated that 9bw inhibited the activity of mitochondrial respiratory complex I. Moreover, we showed that 9bw inhibited growth of NB in vivo. Based on the results of the present study, 9bw is a good candidate as a novel agent for treatment of NB.

Amyloid precursor protein, an androgen-regulated gene, is targeted by RNA-binding protein PSF/SFPQ in neuronal cells.

Amyloid precursor protein (APP) is a representative gene related to Alzheimer's disease (AD). Androgens function by binding to the androgen receptor (AR). Both androgen and RNA-binding protein PSF play a role in the pathology of AD. However, the involvement of AR and PSF in APP regulation in neuron has not been investigated. Here, we explored the regulatory mechanism of APP expression by AR and PSF using neuron-derived cells. We demonstrated that androgen up-regulates the production of APP at the mRNA and protein levels. This induction is enhanced by AR over-expression and inhibited by its silencing. One candidate AR-binding region was identified in the intron region of APP and validated its activity as AR-dependent enhancer by the luciferase assay. Furthermore, the public transcriptome data of brain tissues of mice indicated that APP is regulated by PSF post-transcriptionally. We observed a decreased expression of APP after PSF knockdown and interaction of PSF with the APP transcript. Moreover, we revealed that silencing of PSF inhibited the stability of the APP mRNA. Thus, these results presented a new regulatory mechanism of APP expression by androgen through AR-mediated transcription and PSF at the post-transcriptional level that might be associated with the occurrence of AD.

Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-ß1 on the Malignant Phenotypes of Liver Cancer Cells.

Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. In liver cancer, transforming growth factor (TGF)-ß expression is correlated with tumor grade, and high-grade liver cancer tissues express epithelial-mesenchymal transition markers. TGF-ß1 was reported to be involved in cancer development by transforming precancer cells to cancer stem cells (CSCs). This study aimed to evaluate the effects of TGF-ß1-targeting PI polyamide on the growth of liver cancer cells and CSCs and their TGF-ß1 expression. We analyzed TGF-ß1 expression level after the administration of GB1101, a PI polyamide that targets human TGF-ß1 promoter, and examined its effects on cell proliferation, invasiveness, and TGF-ß1 mRNA expression level. GB1101 treatment dose-dependently decreased TGF-ß1 mRNA levels in HepG2 and HLF cells, and inhibited HepG2 colony formation associated with downregulation of TGF-ß1 mRNA. Although GB1101 did not substantially inhibit the proliferation of HepG2 cells compared to untreated control cells, GB1101 significantly suppressed the invasion of HLF cells, which displayed high expression of CD44, a marker for CSCs. Furthermore, GB1101 significantly inhibited HLF cell sphere formation by inhibiting TGF-ß1 expression, in addition to suppressing the proliferation of HLE and HLF cells. Taken together, GB1101 reduced TGF-ß1 expression in liver cancer cells and suppressed cell invasion; therefore, GB1101 is a novel candidate drug for the treatment of liver cancer.

Identification of new octamer transcription factor 1-target genes upregulated in castration-resistant prostate cancer.

Octamer transcription factor 1 (OCT1) is an androgen receptor (AR)-interacting partner and regulates the expression of target genes in prostate cancer cells. However, the function of OCT1 in castration-resistant prostate cancer (CRPC) is not fully understood. In the present study, we used 22Rv1 cells as AR-positive CRPC model cells to analyze the role of OCT1 in CRPC. We showed that OCT1 knockdown suppressed cell proliferation and migration of 22Rv1 cells. Using microarray analysis, we identified four AR and OCT1-target genes, disks large-associated protein 5 (DLGAP5), kinesin family member 15 (KIF15), non-SMC condensin I complex subunit G (NCAPG), and NDC80 kinetochore complex component (NUF2) in 22Rv1 cells. We observed that knockdown of DLGAP5 and NUF2 suppresses growth and migration of 22Rv1 cells. Furthermore, immunohistochemical analysis showed that positive expression of DLGAP5 in prostate cancer specimens is related to poor cancer-specific survival rates of patients. Notably, enhanced expression of DLGAP5 was observed in CRPC tissues of patients. Thus, our findings suggest that these four genes regulated by the AR/OCT1 complex could have an important role in CRPC progression.

Identification of a novel E-box binding pyrrole-imidazole polyamide inhibiting MYC-driven cell proliferation.

The MYC transcription factor plays a crucial role in the regulation of cell cycle progression, apoptosis, angiogenesis, and cellular transformation. Due to its oncogenic activities and overexpression in a majority of human cancers, it is an interesting target for novel drug therapies. MYC binding to the E-box (5'-CACGTGT-3') sequence at gene promoters contributes to more than 4000 MYC-dependent transcripts. Owing to its importance in MYC regulation, we designed a novel sequence-specific DNA-binding pyrrole-imidazole (PI) polyamide, Myc-5, that recognizes the E-box consensus sequence. Bioinformatics analysis revealed that the Myc-5 binding sequence appeared in 5'- MYC binding E-box sequences at the eIF4G1, CCND1, and CDK4 gene promoters. Furthermore, ChIP coupled with detection by quantitative PCR indicated that Myc-5 has the ability to inhibit MYC binding at the target gene promoters and thus cause downregulation at the mRNA level and protein expression of its target genes in human Burkitt's lymphoma model cell line, P493.6, carrying an inducible MYC repression system and the K562 (human chronic myelogenous leukemia) cell line. Single i.v. injection of Myc-5 at 7.5 mg/kg dose caused significant tumor growth inhibition in a MYC-dependent tumor xenograft model without evidence of toxicity. We report here a compelling rationale for the identification of a PI polyamide that inhibits a part of E-box-mediated MYC downstream gene expression and is a model for showing that phenotype-associated MYC downstream gene targets consequently inhibit MYC-dependent tumor growth.

The oncogenic role of GASC1 in chemically induced mouse skin cancer.

Gene amplified in squamous cell carcinoma (SCC) 1 (GASC1), also known as KDM4C/JMJD2C, encodes a histone demethylase that specifically demethylates lysine residues (H3K9, H3K36, and H1.4K26) and plays a crucial role in the regulation of gene expression as well as in heterochromatin formation. GASC1 is located at human chromosome 9p23-24, where frequent genomic amplification is observed in human esophageal cancer, and its aberrant expression is detected in a variety of human cancers, such as breast, colon, and prostate. Therefore, it is highly likely that GASC1 contributes to the genesis and/or development of cancer. However, there is a lack of direct evidence of GASC1 having an oncogenic function. In this study, we aimed to clarify the role of GASC1 in the skin SCC carcinogenesis. For this purpose, we generated Gasc1-heterozygous mice (Gasc1+/-) with reduced expression of Gasc1. On the basis of our results, Gasc1+/- mice displayed a significantly lower incidence and multiplicity of both benign and malignant tumors induced by the two-stage skin carcinogenesis protocol than wild-type mice. In addition, the volume of carcinoma was significantly lower in Gasc1+/- mice. Consistent with these observations, knocking down of Gasc1 resulted in reduced cell viability of SCC cells in vitro. Our findings clearly demonstrated that GASC1 has an oncogenic role in skin carcinogenesis.

Genome-wide screening of aberrant DNA methylation which associated with gene expression in mouse skin cancers.

Epigenetic alteration of genomic DNA is a common and key process in carcinogenesis. There is considerable evidence indicating that some of the somatic alterations occurring during carcinogenesis in humans also involve the same processes as those observed in mice. Therefore, we analyzed mouse skin cancer tissues induced by the 2-stage carcinogenesis model to identify skin tumor-specific differentially methylated regions (ST-DMRs) during the multistep carcinogenesis process. We have previously identified ST-DMRs using the restriction landmark genomic scanning (RLGS) technique and reported that some of the mouse ST-DMRs were also epigenetically modified in human cancers, such as melanoma, neuroblastoma, and brain tumor. These results encouraged us to pursue global methylation screening in mouse skin carcinogenesis. Using the methylated DNA immunoprecipitation (MeDIP) method combined with the NimbleGen promoter plus CpG island (CpGi) array, we identified 615 ST-DMRs. In combination with global gene expression analysis, 91 of these ST-DMRs were shown to be located on or around the genes differentially expressed between normal skin and tumor tissues, including a candidate human tumor suppressor gene Tfap2e. As observed in human colorectal cancers, Tfap2e was methylated at a CpGi located in intron 3 and downregulated in skin tumors. Our results identified aberrant methylated regions that were associated with gene expression regulation during carcinogenesis, which may indicate critical genetic regions also involved in human carcinogenesis. © 2013 Wiley Periodicals, Inc.

Identification of frequent differentially methylated region in sporadic bladder cancers.

INTRODUCTION: Aberrant methylation levels in the cytosine-phosphate-guanine island (CpGi) region from exon 1 to intron 1 of the zygote arrest 1 (ZAR1) gene have been reported in several types of human cancers, including melanoma, brain tumor, and hepatocellular carcinoma. In the present study, methylation levels at the CpGi of ZAR1 exon 1/intron 1 in bladder cancer specimens were analyzed using mass spectrometry. MATERIALS AND METHODS: Genomic DNA was extracted from 20 sporadic bladder cancers, and the methylation levels at ZAR1 CpGi were quantitatively examined by the MassARRAY EpiTYPER method. RESULT: The methylation levels at specific CpG sites of the ZAR1 CpGi were significantly lower in high-grade bladder cancers than in low-grade tumors. CONCLUSIONS: The results of the present study indicated a decreased methylation level at CpG sites of ZAR1 exon 1/intron 1. CpGi could serve as a biomarker for invasive bladder cancer.

Pyrrole-imidazole polyamide targeted to break fusion sites in TMPRSS2 and ERG gene fusion represses prostate tumor growth.

Aberrant overexpression of ERG induced by the TMPRSS2-ERG gene fusion is likely involved in the development of prostate cancer. Synthetic pyrrole-imidazole (PI) polyamides recognize and attach to the minor groove of DNA with high affinity and specificity. In the present study, we designed a PI polyamide targeting TMPRSS2-ERG translocation breakpoints and assessed its effect on human prostate cancer cells. Our study identified that this PI polyamide repressed the cell and tumor growth of androgen-sensitive LNCaP prostate cancer cells. Targeting of these breakpoint sequences by PI polyamides could be a novel approach for the treatment of prostate cancer.

Inhibition of human osteosarcoma cell migration and invasion by a gene silencer, pyrrole-imidazole polyamide, targeted at the human MMP9 NF-κB binding site.

Osteosarcoma is one of the most prevalent bone tumors, occurring mostly in adolescence. However, no noticeable progress has been achieved in developing new therapeutic agents for this disease. Matrix metalloproteinase 9 (MMP9), a type IV collagenase, is a known anticancer target and is overexpressed in osteosarcomas. MMPs can degrade components of the extracellular matrix and are known to be involved in tumor invasion and metastasis. In the present study, we designed and synthesized a pyrrole-imidazole polyamide (HN.49), a gene-silencing agent that specifically targets the nuclear factor-kappa B (NF-κB) binding site of the human MMP9 promoter. We then examined the effect of HN.49 on the enzyme activity of MMP9 and the migration activity of osteosarcoma cells in vitro. It was clearly shown that HN.49 polyamide reduced the expression level of MMP9 mRNA and the enzymatic activity of MMP-9 in SaOS-2 cells. Moreover, HN.49 polyamide inhibited migration and invasion by SaOS-2 cells in in vitro wound-closure and matrigel-invasion assays. These results indicate that HN.49 may be a potential therapeutic agent for inhibiting the invasion and metastasis of osteosarcoma.

Knockdown of TFAP2E results in rapid G2/M transition in oral squamous cell carcinoma cells.

TFAP2E is a member of the activator protein-2 transcription factor family and acts as a tumor suppressor in several types of cancer. Downregulation of TFAP2E expression is significantly associated with a shorter overall survival period in patients with oral squamous cell carcinoma (OSCC). To evaluate the molecular mechanisms by which TFAP2E suppresses the development or progression of OSCC, the present study investigated the effects of TFAP2E downregulation on OSCC-derived Ca9-22 and HSC-4 cells. The present study demonstrated that small interfering RNA mediated-knockdown of TFAP2E accelerated the proliferation of these OSCC cell lines compared with that in the control group, as determined by the standard water-soluble tetrazolium salt-8 assay. To analyze the cell cycle progression rate, the cell cycle distribution patterns of TFAP2E-knockdown and control cells cultured in the presence of nocodazole, which prevents the completion of mitosis, were analyzed by fluorescence-activated cell sorting at different time points. When analyzing cellular DNA contents, no major differences in cell cycle profiles were observed; however, the rate of increase in cells positive for histone H3 Serine 28 phosphorylation, a standard molecular marker of early M phase, was significantly higher in TFAP2E-knockdown cells than in the control cells. Collectively, these results suggested that TFAP2E may attenuate the proliferation of OSCC cells by regulating G2/M transition.

Identification of aberrant methylation regions in neuroblastoma by screening of tissue-specific differentially methylated regions.

BACKGROUND: The identification of tissue-specific differentially methylated regions (tDMRs) is key to our understanding of mammalian development. Research has indicated that tDMRs are aberrantly methylated in cancer and may affect the oncogenic process. PROCEDURE: We used the MassARRAY EpiTYPER system to determine the quantitative methylation levels of seven neuroblastomas (NBs) and two control adrenal medullas at 12 conserved tDMRs. A second sample set of 19 NBs was also analyzed. Statistical analysis was carried out to determine the relationship of the quantitative methylation levels to other prognostic factors in these sample sets. RESULTS: Screening of 12 tDMRs revealed 2 genomic regions (SLC16A5 and ZNF206) with frequent aberrant methylation patterns in NB. The methylation levels of SLC16A5 and ZNF206 were low compared to the control adrenal medullas. The SLC16A5 methylation level (cut-off point, 13.25%) was associated with age at diagnosis, disease stage, and Shimada classification but not with MYCN amplification. The ZNF206 methylation level (cut-off point, 68.80%) was associated with all of the prognostic factors analyzed. Although the methylation levels at these regions did not reach statistical significance in their association with prognosis in mono-variant analysis, patients with both hypomethylation of SLC16A5 and hypermethylation of ZNF206 had a significantly prolonged event-free survival, when these two variables were analyzed together. CONCLUSIONS: We demonstrated that two tDMRs frequently displayed altered methylation patterns in the NB genome, suggesting their distinct involvement in NB development/differentiation. The combined analysis of these two regions could serve as a diagnostic biomarker for poor clinical outcome.

Tension force causes cell cycle arrest at G2/M phase in osteocyte-like cell line MLO-Y4.

Bone remodelling is the process of bone resorption and formation, necessary to maintain bone structure or for adaptation to new conditions. Mechanical loadings, such as exercise, weight bearing and orthodontic force, play important roles in bone remodelling. During the remodelling process, osteocytes play crucial roles as mechanosensors to regulate osteoblasts and osteoclasts. However, the precise molecular mechanisms by which the mechanical stimuli affect the function of osteocytes remain unclear. In the present study, we analysed viability, cell cycle distribution and gene expression pattern of murine osteocyte-like MLO-Y4 cells exposed to tension force (TF). Cells were subjected to TF with 18% elongation at 6 cycles/min for 24 h using Flexcer Strain Unit (FX-3000). We found that TF stimulation induced cell cycle arrest at G2/M phase but not cell death in MLO-Y4 cells. Differentially expressed genes (DEGs) between TF-stimulated and unstimulated cells were identified by microarray analysis, and a marked increase in glutathione-S-transferase α (GSTA) family gene expression was observed in TF-stimulated cells. Enrichment analysis for the DEGs revealed that Gene Ontology (GO) terms and Kyoto Encyclopedia Genes and Genomes (KEGG) pathways related to the stress response were significantly enriched among the upregulated genes following TF. Consistent with these results, the production of reactive oxygen species (ROS) was elevated in TF-stimulated cells. Activation of the tumour suppressor p53, and upregulation of its downstream target GADD45A, were also observed in the stimulated cells. As GADD45A has been implicated in the promotion of G2/M cell cycle arrest, these observations may suggest that TF stress leads to G2/M arrest at least in part in a p53-dependent manner.

Recovery from the damage of cranial radiation modulated by memantine, an NMDA receptor antagonist, combined with hyperbaric oxygen therapy.

BACKGROUND: Radiotherapy is an important treatment option for central nervous system malignancies. However, cranial radiation induces hippocampal dysfunction and white matter injury; this leads to cognitive dysfunction, and results in a reduced quality of life in patients. Excitatory glutamate signaling through N-methyl-d-aspartate receptors (NMDARs) plays a central role both in hippocampal neurogenesis and in the myelination of oligodendrocytes in the cerebrum. METHODS: We provide a method for quantifying neurogenesis in human subjects in live brain during cancer therapy. Neuroimaging using originally created behavioral tasks was employed to examine human hippocampal memory pathway in patients with brain disorders. RESULTS: Treatment with memantine, a non-competitive NMDAR antagonist, reversed impairment in hippocampal pattern separation networks as detected by functional magnetic resonance imaging. Hyperbaric preconditioning of the patients just before radiotherapy with memantine mostly reversed white matter injury as detected by whole brain analysis with Tract-Based Spatial Statics. Neuromodulation combined with the administration of hyperbaric oxygen therapy and memantine during radiotherapy facilitated the restoration of hippocampal function and white matter integrity, and improved higher cognitive function in patients receiving cranial radiation. CONCLUSIONS: The method described herein, for diagnosis of hippocampal dysfunction, and therapeutic intervention can be utilized to restore some of the cognitive decline experienced by patients who have received cranial radiation. The underlying mechanism of restoration is the production of new neurons, which enhances functionality in pattern separation networks in the hippocampi, resulting in an increase in cognitive score, and restoration of microstructural integrity of white matter tracts revealed by Tract-Based Spatial Statics Analysis.