The histone demethylase lysine‐specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of ...H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear. Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48‐linked deubiquitin and stability. Interestingly, we found c‐Myc was a key downstream effector of the USP1‐KDM4A/androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC.
This study identifies USP1 as a critical deubiquitinase for stabilizing KDM4A, thereby promoting prostate cancer growth and tumorigenesis. Targeting KDM4A stabilization through pharmacological inhibition of USP1 by ML323 could thus open an avenue for therapeutic intervention in prostate cancer patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
It remains difficult to distinguish tumor recurrence from radiation necrosis after brain tumor therapy. Here we show that these lesions can be distinguished using the amide proton transfer (APT) ...magnetic resonance imaging (MRI) signals of endogenous cellular proteins and peptides as an imaging biomarker. When comparing two models of orthotopic glioma (SF188/V+ glioma and 9L gliosarcoma) with a model of radiation necrosis in rats, we could clearly differentiate viable glioma (hyperintense) from radiation necrosis (hypointense to isointense) by APT MRI. When we irradiated rats with U87MG gliomas, the APT signals in the irradiated tumors had decreased substantially by 3 d and 6 d after radiation. The amide protons that can be detected by APT provide a unique and noninvasive MRI biomarker for distinguishing viable malignancy from radiation necrosis and predicting tumor response to therapy.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Simulated water samples of 3 kinds of preservatives and 4 kinds of sweeteners were formulated by using orthogonal design. Kernel independent component analysis (KICA) was used to process the UV ...spectra of the simulated water samples and the beverages added different amounts of the additive standards, then the independent components (ICs), i. e. the UV spectral profiles of the additives, and the ICs' coefficient matrices were used to establish UV-KICA-SVR prediction model of the simulated preservatives and sweeteners solutions using support vector regression (SVR) analysis. The standards added beverages samples were obtained by adding different amounts level of additives in carbonated beverages, their UV spectra were processed by KICA, then IC information represented to the additives and other sample matrix were obtained, and the sample background can be deducted by removing the corresponding IC, other ICs' coefficient matrices were used to estimate the amounts of the additives in the standard added beverage s
Radiation necrosis is a major complication of radiation therapy. We explore the features of radiation-induced brain necrosis in the rat, using multiple MRI approaches, including T(1), T(2), apparent ...diffusion constant (ADC), cerebral blood flow (CBF), magnetization transfer ratio (MTR), and amide proton transfer (APT) of endogenous mobile proteins and peptides.
Adult rats (Fischer 344; n = 15) were irradiated with a single, well-collimated X-ray beam (40 Gy; 10 × 10 mm(2)) in the left brain hemisphere. MRI was acquired on a 4.7-T animal scanner at ~25 weeks' postradiation. The MRI signals of necrotic cores and perinecrotic regions were assessed with a one-way analysis of variance. Histological evaluation was accomplished with hematoxylin and eosin staining.
ADC and CBF MRI could separate perinecrotic and contralateral normal brain tissue (p < 0.01 and < 0.05, respectively), whereas T(1), T(2), MTR, and APT could not. MRI signal intensities were significantly lower in the necrotic core than in normal brain for CBF (p < 0.001) and APT (p < 0.01) and insignificantly higher or lower for T(1), T(2), MTR, and ADC. Histological results demonstrated coagulative necrosis within the necrotic core and reactive astrogliosis and vascular damage within the perinecrotic region.
ADC and CBF are promising imaging biomarkers for identifying perinecrotic regions, whereas CBF and APT are promising for identifying necrotic cores.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Purpose:
In the radiopharmaceutical therapy approach to the fight against cancer, in particular when it comes to translating laboratory results to the clinical setting, modeling has served as an ...invaluable tool for guidance and for understanding the processes operating at the cellular level and how these relate to macroscopic observables. Tumor control probability (TCP) is the dosimetric end point quantity of choice which relates to experimental and clinical data: it requires knowledge of individual cellular absorbed doses since it depends on the assessment of the treatment’s ability to kill each and every cell. Macroscopic tumors, seen in both clinical and experimental studies, contain too many cells to be modeled individually in Monte Carlo simulation; yet, in particular for low ratios of decays to cells, a cell-based model that does not smooth away statistical considerations associated with low activity is a necessity. The authors present here an adaptation of the simple sphere-based model from which cellular level dosimetry for macroscopic tumors and their end point quantities, such as TCP, may be extrapolated more reliably.
Methods:
Ten homogenous spheres representing tumors of different sizes were constructed inGEANT4. The radionuclide 131I was randomly allowed to decay for each model size and for seven different ratios of number of decays to number of cells, N
r
: 1000, 500, 200, 100, 50, 20, and 10 decays per cell. The deposited energy was collected in radial bins and divided by the bin mass to obtain the average bin absorbed dose. To simulate a cellular model, the number of cells present in each bin was calculated and an absorbed dose attributed to each cell equal to the bin average absorbed dose with a randomly determined adjustment based on a Gaussian probability distribution with a width equal to the statistical uncertainty consistent with the ratio of decays to cells, i.e., equal to
N
r
-
1
/
2
. From dose volume histograms the surviving fraction of cells, equivalent uniform dose (EUD), and TCP for the different scenarios were calculated. Comparably sized spherical models containing individual spherical cells (15 μm diameter) in hexagonal lattices were constructed, and Monte Carlo simulations were executed for all the same previous scenarios. The dosimetric quantities were calculated and compared to the adjusted simple sphere model results. The model was then applied to the Bortezomib-induced enzyme-targeted radiotherapy (BETR) strategy of targeting Epstein-Barr virus (EBV)-expressing cancers.
Results:
The TCP values were comparable to within 2% between the adjusted simple sphere and full cellular models. Additionally, models were generated for a nonuniform distribution of activity, and results were compared between the adjusted spherical and cellular models with similar comparability. The TCP values from the experimental macroscopic tumor results were consistent with the experimental observations for BETR-treated 1 g EBV-expressing lymphoma tumors in mice.
Conclusions:
The adjusted spherical model presented here provides more accurate TCP values than simple spheres, on par with full cellular Monte Carlo simulations while maintaining the simplicity of the simple sphere model. This model provides a basis for complementing and understanding laboratory and clinical results pertaining to radiopharmaceutical therapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
SF188/V+ is a highly vascular human glioma model that is based on transfection of vascular endothelial growth factor (VEGF) cDNA into SF188/V− cells. This study aims to assess its growth and ...vascularity properties in vivo in a rat model. Thirty-two adult rats were inoculated with SF188/V+ tumor cells, and, for comparison, five were inoculated with SF188/V− tumor cells. Several conventional magnetic resonance imaging (MRI) sequences were acquired, and several quantitative structural (T
2
and T
1
), functional isotropic apparent diffusion coefficient (ADC) and blood flow, and molecular protein and peptide-based amide proton transfer (APT) MRI parameters were mapped on a 4.7 T animal scanner. In rats inoculated with SF188/V+ tumor cells, conventional T
2
-weighted images showed a highly heterogeneous tumor mass, and post-contrast T
1
-weighted images showed a heterogeneous, strong enhancement of the mass. There were moderate increases in T
2
, T
1
, and ADC, and large increases in blood flow and APT in the tumor, compared to contralateral brain tissue. Microscopic examination revealed prominent vascularity and hemorrhage in the VEGF-secreting xenografts as compared to controls, and immunohistochemical staining confirmed increased expression of VEGF in tumor xenografts. Our results indicate that the SF188/V+ glioma model exhibits some MRI and histopathology features that closely resemble human glioblastoma.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The histone demethylase JMJD1A plays a key functional role in spermatogenesis, sex determination, stem cell renewal, and cancer via removing mono- and di-methyl groups from H3K9 to epigenetically ...control gene expression. However, its role in prostate cancer progression remains unclear. Here, we found JMJD1A was significantly elevated in prostate cancer tissue compared with matched normal tissue. Ectopic JMJD1A expression in prostate cancer cells promoted proliferation, migration, and invasion
, and tumorigenesis
; JMJD1A knockdown exhibited the opposite effects. Mechanically, we revealed that JMJD1A directly interacted with the Snail gene promoter and regulated its transcriptional activity, promoting prostate cancer progression both
and
. Furthermore, we found that JMJD1A transcriptionally activated Snail expression via H3K9me1 and H3K9me2 demethylation at its special promoter region. In summary, our studies reveal JMJD1A plays an important role in regulating proliferation and progression of prostate cancer cells though Snail, and thus highlight JMJD1A as potential therapeutic target for advanced prostate cancer. IMPLICATIONS: Our studies identify that JMJD1A promotes the proliferation and progression of prostate cancer cells through enabling Snail transcriptional activation, and thus highlight JMJD1A as potential therapeutic target for advanced prostate cancer.
Purpose: EBV and other herpesviruses are associated with a variety of malignancies. The EBV thymidine kinase (TK) is either not expressed
or is expressed at very low levels in EBV-associated tumors. ...However, EBV-TK expression can be induced in vitro with several chemotherapeutic agents that promote viral lytic induction. The goal of this study is to image EBV-associated
tumors by induction of viral TK expression with radiolabeled 2′-fluoro-2′-deoxy-β- d -5-iodouracil-arabinofuranoside (FIAU).
Experimental Design: Immunoblot, luciferase reporter assay, and in vitro assay with 14 CFIAU were used to show the effects of bortezomib on the induction of lytic gene expression of EBV-associated tumor cells.
In vivo imaging and ex vivo biodistribution studies with 125 IFIAU on EBV-associated tumors were done to visualize and confirm, respectively, the EBV(+) tumor–specific effects of bortezomib.
Results: In vitro assays with 14 CFIAU and ex vivo biodistribution studies with 125 IFIAU showed that uptake and retention of radiolabeled FIAU was specific for cells that express EBV-TK. Planar gamma imaging
of EBV(+) Burkitt's lymphoma xenografts in severe combined immunodeficient mice showed 125 IFIAU localization within tumors following treatment with bortezomib.
Conclusions: These results indicate the feasibility of imaging chemotherapy-mediated viral lytic induction by radiopharmaceutical-based
techniques such as single photon emission computed tomography and positron emission tomography.
PURPOSE OF REVIEWProstate cancer (PCa) demonstrates characteristic changes in metabolism and bioenergetics in the transition from benign to malignant tissue. It is feasible that some of these changes ...may be targetable for therapeutic purposes. This review will highlight some of the current metabolically targeted therapies being investigated for the treatment of prostate cancer.
RECENT FINDINGSThe transition from benign to malignant prostate cells is characterized by decreased intracellular zinc concentration and subsequent release of inhibition of the tricarboxylic acid cycle enzyme m-aconitase, which leads to the decrease in citrate concentration within the cancer tissue. Instead of the largely glycolytic phenotype exhibited by most cancers, PCa relies on glutamine and lipids for survival and proliferation. Early studies are beginning to demonstrate that targeting some of the upregulated pathways with inhibitors of key enzymes, such as glutaminase, fatty acid synthase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, hexokinase, zinc transport, or complex I in the mitochondria may have significant metabolic effects and therapeutic potential.
SUMMARYThe unique metabolic profile of PCa allows for many potential avenues of treatment. Future studies will continue to test if the metabolic characterization and treatment of PCa could be an important approach to provide personalized treatment for the disease.
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