RaRaCl
is the first alpha-particle emitting radiopharmaceutical to be used for castration-resistant prostate cancer patients with bone metastases because of its excellent therapeutic effects.
...RaRaCl
is excreted via the intestine into feces, and some is absorbed from the intestine into the blood, which may be undesirable in terms of the exposure to radiation. Recently, we showed that a complex of myo-inositol-hexakisphosphate (InsP6) with zinc is a useful decorporation agent against radiostrontium. In this study, we hypothesized that Zn-InsP6 could bind to not only strontium but also to radium, and could inhibit the absorption of radium from the intestine. In in vitro binding experiments, Zn-InsP6 showed a high binding affinity for radium. In in vivo biodistribution experiments by intravenous injection of
RaRaCl
after treatment of Zn-InsP6, mice treated with Zn-InsP6 showed significantly lower bone accumulation of radioactivity (34.82 ± 1.83%Dose/g) than the mice in the non-treatment control group (40.30 ± 2.78%Dose/g) at 48 h postinjection. These results indicate that Zn-InsP6 bound radium in the intestine and inhibited the absorption of radium into the blood. Therefore, the insoluble Zn-InsP6 complex has high potential to decrease the side effects of
RaRaCl
.
The objective of the current study is to evaluate the potency of halogen-furan-2(5
H
)-one-type derivatives against human cancer cell lines. Four known bromofuran-2(5
H
)-one-type derivatives, as ...well as five new and two known bromo-4-(phenylamino)furan-2(5
H
)-one-type compounds and six novel and two known halogen-4-alkyl-5-phenyl-3-(phenylamino)furan-2(5
H
)-one-type derivatives, were synthesized and evaluated for their anticancer activity against prostate (PC-3) and colon (HCT-116) human cancer cell lines. The results showed that only the bromofuran-2(5
H
)-ones were cytotoxic in both cell lines. Three of these displayed particularly useful antiproliferative activities, in both cancer cells evaluated. (
E
)-5-(Bromomethylene)furan-2-(5
H
)-one was the most active against PC-3 (IC
50
0.93 ± 0.02 μM) while 3,4-dibromofuran-2(5
H
)-one was the most active against HCT-116 (IC
50
0.4 ± 0.04 μM). Furthermore, flow cytometry studies revealed that the bromofuran-2(5
H
)-ones induced cell death by apoptosis. Also, it was found that the cytotoxic furanones induced lipid peroxidation, determined by TBARS assay. Thus, cytotoxicity of the active compounds could be associated with ROS production. Additionally, it must be taken into account that all cytotoxic compounds contain an electrophilic carbon atom in position 4, which can explain, through a non-specific reactivity with nucleophiles, the cytotoxic activity of these compounds.
Graphic abstract
Zika virus (ZIKV) is an arboviral infection that has been shown to be sexually transmitted. The study outlined herein aims to determine if accessory sex glands and epididymal epithelial cells are ...sources of viral persistence in subacute and chronic ZIKV infection, and if infection of these organs is important in sexual transmission during long-term (chronic) infection. Male interferon type I receptor knockout (Ifnar
) mice were challenged with ZIKV and reproductive tissues were harvested 14 and 35 days post infection (DPI) for inoculation studies and 14, 35 and 70 DPI for histopathology. Artificial insemination fluid derived from epididymal flush and seminal plasma from the prostate and seminal vesicle was obtained from ZIKV inoculated and sham-infected males. Naïve interferon type I and II receptor knockout (AG129) female mice were pre-treated with progesterone and inoculated intravaginally with artificial insemination fluid from ZIKV-infected males. ZIKV RNA was detected in the artificial insemination fluid generated from epididymal flush or seminal plasma from ZIKV infected males at 14 and 35 DPI. ZIKV antigens were only detected in seminiferous tubules at 14 DPI. Epididymal epithelial cells did not show ZIKV antigen immunoreactivity at 14, 35 or 70 DPI. Severe fibrosing orchitis (end stage orchitis) was observed at 35 and 70 DPI. Mild inflammation and peri-tubular fibrosis were observed in the epididymis following clearance of virus. Viral RNA was not detected by PCR in whole blood samples of females from any intravaginal experimental group and only detected in 20% of subcutaneously inoculated animals (derived from 1 experimentally infected male) at 35 DPI. While ZIKV RNA and antigens can be detected in the male reproductive tract at 14 DPI and RNA can also be detected at 35 DPI, intravaginal inoculation of artificial insemination fluid from these time-points failed to result in viremia in naïve females inoculated intravaginally. These studies support the hypothesis that epididymal epithelial cells are critical to sexual transmission in immunocompromised mice. Additionally, acute but not chronic male reproductive tract infection with ZIKV results in infectious virus capable of being sexually transmitted in mice.
We identified a new human prostate cancer oncogene, nucleolar protein 6 (NOL6), and screened for microRNAs that interfere with its expression in prostate cancer cells. A NOL6 shRNA plasmid was ...constructed and packaged into lentivirus to infect PC-3 cells. The ability of cell proliferation was evaluated by cell counting and colony formation. Cell cycle progression and apoptosis of PC-3 cells were detected by flow cytometry. A retrieval database was used to screen possible target microRNAs, and the effect of target miRNA overexpression on PC-3 cells was observed. The results showed that after NOL6 gene knockdown, PC-3 cell mitosis was blocked, proliferation was decreased, and the number of apoptotic cells were increased. The microRNA, hsa-miR-590-3p, that can regulate the NOL6 gene expression was identified. Overexpression of miR-590-3p in PC-3 cells by synthetic mimics resulted in abnormal mitosis, decreased cell proliferation, and an increase in apoptosis. In summary, we identified NOL6 as a novel oncogene in the human prostate cancer PC-3 cell line. The miRNA miR-590-3p interferes with NOL6 expression making it a potential treatment for prostate cancer.
Improvement of the accuracy of dosimetry in radionuclide therapy has the potential to increase patient safety and therapeutic outcomes. Although positron emission tomography (PET) is ideally suited ...for acquisition of dosimetric data because PET is inherently quantitative and offers high sensitivity and spatial resolution, it is not directly applicable for this purpose because common therapeutic radionuclides lack the necessary positron emission. This work reports on the synthesis of dual‐nuclide labeled radiopharmaceuticals with therapeutic and PET functionality, which are based on common and widely available metal radionuclides. Dual‐chelator conjugates, featuring interlinked cyclen‐ and triazacyclononane‐based polyphosphinates DOTPI and TRAP, allow for strictly regioselective complexation of therapeutic (e.g., 177Lu, 90Y, or 213Bi) and PET (e.g., 68Ga) radiometals in the same molecular framework by exploiting the orthogonal metal ion selectivity of these chelators (DOTPI: large cations, such as lanthanide(III) ions; TRAP: small trivalent ions, such as GaIII). Such DOTPI–TRAP conjugates were decorated with 3 Gly‐urea‐Lys (KuE) motifs for targeting prostate‐specific membrane antigen (PSMA), employing Cu‐catalyzed (CuAAC) as well as strain‐promoted (SPAAC) click chemistry. These were labeled with 177Lu or 213Bi and 68Ga and used for in vivo imaging of LNCaP (human prostate carcinoma) tumor xenografts in SCID mice by PET, thus proving practical applicability of the concept.
Take two: Dual‐nuclide labeled radiopharmaceuticals with therapeutic and PET functionality, derived from common and widely available metal radionuclides, enable a precise PET‐based dosimetry for improvement of individual therapeutic outcome and increased patient safety in molecular radiotherapy.
Purpose
To investigate whether building a knowledge‐based planning (KBP) model with prostate bed plans constructed from constrained hierarchical optimization (CHO) would result in more efficient ...model construction with more consistent output than a model built using plans from a traditional, trial‐and‐error‐based optimization (TEO) technique.
Methods
Three KBP models were constructed from plans from subsets of 58 post‐prostatectomy patients treated with intensity‐modulated radiation therapy. TEO54 was built from 54 TEO plans, selected to represent typical clinical variations in target and organ‐at‐risk sizes and shapes. CHO30 and TEO30 were built from the same 30 patients populated with CHO and TEO plans, respectively. The three models were each applied to a new set of 18 patient scans and dose–volume histogram estimates (DVHEs) were generated for rectal and bladder walls and compared for each patient.
Results
CHO30 resulted in a significantly tighter range in DVHEs (P < 0.01) for both the rectal and bladder walls compared with either of the TEO models, indicating less uncertainty in the dose estimation. Plans resulting from KBP optimization using each model were very similar.
Conclusion
Populating a KBP model with CHO data resulted in a high quality model. Since CHO plans can be generated automatically offline in a process that necessitates little to no user interaction, a CHO‐KBP model can quickly adapt to changes in plan evaluation criteria or planning techniques without the need to wait to accrue sufficient numbers of clinical TEO plans. This may facilitate the use of KBP approaches for initial or ongoing quality assurance procedures and plan quality audits.
Objectives
To evaluate musculoskeletal (MSK) radiologist whole-body magnetic resonance imaging (WBMRI) practice patterns in an effort to better understand current MSK clinical utilization and the ...need for standardized coding.
Methods
A 12-question survey was created in Survey Monkey®. The survey was e-mailed to Society of Skeletal Radiology (SSR) members on September 19, 2018. The survey included questions on SSR member demographics and on their experience with WBMRI.
Results
One hundred sixty-four of 1454 (11%) SSR members responded to the survey. A minority (32%;
n
= 52/164) of respondents reported that their institutions routinely perform WBMRI. The most common indication was multiple myeloma (78%,
n
= 51/65). The most commonly utilized sequences were coronal short tau inversion recovery (STIR) (79%,
n
= 52/66) and coronal T1 without fat saturation (73%,
n
= 48/66). A large proportion of respondents (48%,
n
= 31/64) did not know the code used for billing WBMRI at their institutions. Of the remaining respondents, 23% (
n
= 15/64) reported use of the bone marrow MRI code, 16% (
n
= 10/64) the chest/abdomen/pelvis combination code, and 9% (
n
= 6/64) the unlisted MRI procedure code.
Conclusion
There is variation in who is responsible for the protocol and interpretation of WBMRI, as well as how the exam is performed and how the exam is coded, which raise barriers to broad implementation. Recent WBMRI guidelines for multiple myeloma and prostate cancer can mitigate many of these barriers, but they do not address the coding and reimbursement challenges. Collaborative multi-society development of a new CPT® code for WBMRI may be a worthwhile endeavor.
A novel approach for chemoselective synthesis of functionalized benzo
g
thiazolo3,2-
a
quinolones from dithioacetals, cysteamine hydrochloride, 2-hydroxy-1,4-naphthoquinone, and aromatic aldehydes in ...ethanol is described. All products were tested in vitro for their cytotoxic effects on lung, breast, and prostate cancer cells.
Graphical abstract
Display omitted
•p-Nitrophenol interacts with FKBP51, a positive regulator of AR signaling.•Structural analysis reveals p-nitrophenol occupies the FK1 pocket of FKBP51.•p-Nitrophenol suppresses AR ...signaling possibly through blocking the FK1 pocket.
The compound p-nitrophenol, which shows the anti-androgenic activity, can easily become anthropogenic pollutants and pose a threat to the environment and human health. Previous work indicates that the anti-androgenic mechanism of p-nitrophenol is complex and may involve several components in the AR signaling pathway, but the molecular details of how p-nitrophenol inhibits AR signaling are still not quite clear. Here, we characterized p-nitrophenol binds to the FK1 domain of an AR positive regulator FKBP51 with micromolar affinity and structural analysis of FK1 domain in complex with p-nitrophenol revealed that p-nitrophenol occupies a hydrophobic FK1 pocket that is vital for AR activity enhancement. Molecular dynamics simulation indicated that p-nitrophenol is stably bound to the FK1 pocket and the hotspot residues that involved p-nitrophenol binding are mainly hydrophobic and overlap with the AR interaction site. Furthermore, we showed that p-nitrophenol inhibits the androgen-dependent growth of human prostate cancer cells, possibly through down-regulating the expression levels of AR activated downstream genes. Taken together, our data suggests that p-nitrophenol suppresses the AR signaling pathway at least in part by blocking the interaction between AR and its positive regulator FKBP51. We believe that our findings could provide new guidelines for assessing the potential health effects of p-nitrophenol.
NMR-Based Prostate Cancer Metabolomics Euceda, Leslie R; Andersen, Maria K; Tessem, May-Britt ...
Methods in molecular biology (Clifton, N.J.),
01/2018, Letnik:
1786
Journal Article
Odprti dostop
Prostate cancer is the second most common malignancy, and the fifth leading cause of cancer-related death among men, worldwide. A major unsolved clinical challenge in prostate cancer is the ability ...to accurately distinguish indolent cancer types from the aggressive ones. Reprogramming of metabolism is now a widely accepted hallmark of cancer development, where cancer cells must be able to convert nutrients to biomass while maintaining energy production. Metabolomics is the large-scale study of small molecules, commonly known as metabolites, within cells, biofluids, tissues, or organisms. Nuclear magnetic resonance (NMR) spectroscopy is commonly applied in metabolomics studies of cancer. This chapter provides protocols for NMR-based metabolomics of cell cultures, biofluids (serum and urine), and intact tissue, with concurrent advice for optimal biobanking and sample preparation procedures.
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