The presence of radiotoxic 210Po and 210Pb in Ukrainian wild medicinal plants and the assessment of related dose and cancer risk.

Herbal plants are considered natural pharmaceuticals but also accumulate chemical elements and compounds at high levels. 210Po and 210Pb are highly radiotoxic and may cause carcinogenesis due to ionizing radiation. Thirteen of the most popular wild-growing herbaceous plant species, mostly included in the European Pharmacopoeia, were collected across Ukraine. 210Po and 210Pb were determined in the medicinal plants, and their radiotoxicity and cancer risk were calculated. The results of 210Po activities measured in herbal raw material ranged from 2.28 Bq kg-1 dw (where dw is dry weight) in herb of common horsetail (Equisetum arvense L.) collected near Lviv to 37.7 Bq kg-1 dw in leaves of common birch (Betula pendula Roth.) from Rava Ruska. The activity concentrations of 210Pb varied from 0.44 Bq kg-1 dw in leaves of common birch from Starokostyantyniv to 28.4 Bq kg-1 dw in leaves of common birch from Mizhhirya. There were statistically significant differences between 210Po and 210Pb content in flowers, leaves, and aerial portions. The studies indicated that the estimated annual effective radiation dose from Ukrainian herbs consumption was low, ranging 5.00-82.6 µSv from 210Po and 0.56-35.8 µSv from 210Pb, while the cancer morbidity and mortality risk ranged from 10-4 to 10-6. The presented data indicated no radiological risk related to using herbal plant materials.

On 210Po and 210Pb in algae diet supplements - The assessed radiation hazard of aquatic superfoods.

Algae are believed to give health benefits. However, the studies showed they contain toxic elements, including radionuclides, and may affect human health. The study presents the values of activity concentrations of 210Po and 210Pb in the algae supplements available worldwide for adults. The activity concentrations (Bq/kg dw) ranged from 0.07 to 14.5 (210Po) and from 0.06 to 8.48 (210Pb). Also, the effective radiation doses and the cancer risk from 210Po and 210Pb decay ingested with analyzed algal supplements have been assessed. The highest values of annual effective doses have been estimated for 210Po in the recommended portion of Spirulina (Arthrospira platensis) from China (59.7 µSv/year) and Diatomaceous earth from the USA (50.4 µSv/year). The cancer morbidity and mortality risk ranged from 10-4 to 10-8. The study indicated the activity concentrations of 210Po and 210Pb were low, and algae supplements for human consumption could be considered safe food.

Comparison of contrast-enhanced videofluoroscopy to unenhanced dynamic MRI in minor patients following surgical correction of velopharyngeal dysfunction.

OBJECTIVES: To compare dynamic magnetic resonance imaging (MRI) with videofluoroscopy (VFS) regarding image quality and assessment of gap size between soft palate (SP) and posterior pharyngeal wall (PPW) in children and adolescents following surgical correction of velopharyngeal dysfunction (VPD). METHODS: Twenty-one patients undergoing unenhanced 3-T MRI and contrast-enhanced VFS were included in this IRB-approved prospective study. The MRI scan protocol comprised refocused gradient-echo sequences in transverse and sagittal planes during speech, with TE 1.97 ms, TR 3.95 ms, flip angle 8°, matrix size 128 × 128, and 5-mm slice thickness. Radial k-space sampling and sliding window reconstruction were used to achieve an image acquisition rate of 28 frames per second (fps). VFS with 30 fps was similarly performed in both planes. Closure of the velopharyngeal port during phonation was evaluated by two experienced radiologists. RESULTS: Eleven (52.4%) patients displayed a complete closure, whereas ten (47.6%) patients showed a post-operative gap during speech. VFS and MRI equally identified the cases with persistent or recurrent VPD. Differences in SP-PPW distance between VFS (3.9 ± 1.6 mm) and MRI (4.1 ± 1.5 mm) were not statistically significant (p = 0.5). The subjective overall image quality of MRI was rated inferior (p < 0.001) compared with VFS, with almost perfect inter-rater agreement (κ = 0.90). The presence of susceptibility artifacts did not limit anatomical measurements. CONCLUSION: Dynamic MRI is equally reliable as VFS to assess persistent or recurrent inadequate velum closure in patients following surgical treatment of VPD. KEY POINTS: • Unenhanced 3-T dynamic MRI and contrast-enhanced videofluoroscopy are equally useful for the identification of patients with incomplete velopharyngeal closure during speech. • MRI using refocused gradient-echo acquisition with radial k-space sampling and sliding window reconstruction generates diagnostic images with 28 frames per second. • MRI can offer a radiation-free alternative to currently established videofluoroscopy for young patients.

Golden-Angle Radial Sparse Parallel (GRASP) MRI differentiates head & neck paragangliomas from schwannomas.

PURPOSE: The aim of this study was to demonstrate the value of DCE MRI with high spatiotemporal resolution (GRASP) for differentiating paragangliomas and schwannomas in the head and neck. METHODS: In a retrospective PACS search of in total 410 patients who had undergone head & neck GRASP-MRI, we identified 6 patients with biopsy proven cervical paragangliomas (n = 3) and schwannomas (n = 3). Conventional MRI features were evaluated, lesion size was determined. Postprocessing in 4D-GRASP datasets was performed (1) based on reconstructions with a temporal resolution (Tres) of 4.1 s, qualitative time-intensity curve classification and semiquantitative parameter (Tpeak, PH, ERmax and Slopemax) analysis, and (2) voxel-based mapping and qualitative and semiquantitative perfusion modeling based on reconstructions with a Tres of 1.6 s. Additionally, GRASP perfusion analysis was performed in another set of 5 patients with presumed cervical paragangliomas (n = 3) and schwannomas (n = 2) based on conventional imaging criteria and was correlated with conventional imaging findings. Due to the small sample size, both groups were compared qualitatively. RESULTS: In the time intensity curve classification of 4D GRASP reconstructions (Tres 4.1 s), biopsy proven paragangliomas were consistently characterized by a type-III rapid inflow wash-out pattern, compared to a type-I inflow pattern in the schwannoma group. In both temporal resolutions, semiquantitative analysis of time intensity curves demonstrated rapid wash-in, wash-out, and higher peak signal intensities in paragangliomas compared to schwannomas. In 5 presumed (non-biopsy-proven) paragangliomas and schwannomas, time intensity curves improved diagnostic certainty. CONCLUSIONS: Visual time intensity curve classification and semi-quantitative analysis of GRASP-MRI were, in this small retrospective series, sufficient to differentiate cervical paragangliomas from schwannomas. Utilization of this technique may further improve diagnostic confidence in lesions lacking conventional imaging features.

Dynamic Contrast-Enhanced MRI to Differentiate Parotid Neoplasms Using Golden-Angle Radial Sparse Parallel Imaging.

BACKGROUND AND PURPOSE: Conventional imaging frequently shows overlapping features between benign and malignant parotid neoplasms. We investigated dynamic contrast-enhanced MR imaging using golden-angle radial sparse parallel imaging in differentiating parotid neoplasms. MATERIALS AND METHODS: For this retrospective study, 41 consecutive parotid neoplasms were imaged with dynamic contrast-enhanced MR imaging with golden-angle radial sparse parallel imaging using 1-mm in-plane resolution. The temporal resolution was 3.4 seconds for 78.2 seconds and 8.8 seconds for the remaining acquisition. Three readers retrospectively and independently created and classified time-intensity curves as follows: 1) continuous wash-in; 2) rapid wash-in, subsequent plateau; and 3) rapid wash-in with washout. Additionally, time-intensity curve-derived semiquantitative metrics normalized to the ipsilateral common carotid artery were recorded. Diagnostic performance for the prediction of neoplasm type and malignancy was assessed. Subset multivariate analysis (n = 32) combined semiquantitative time-intensity curve metrics with ADC values. RESULTS: Independent time-intensity curve classification of the 41 neoplasms produced moderate-to-substantial interreader agreement (κ = 0.50-0.79). The time-intensity curve classification threshold of ≥2 predicted malignancy with a positive predictive value of 56.0%-66.7%, and a negative predictive value of 92.0%-100%. The time-intensity curve classification threshold of <2 predicted pleomorphic adenoma with a positive predictive value of 87.0%-95.0% and a negative predictive value of 76.0%-95.0%. For all readers, type 2 and 3 curves were associated with malignant neoplasms (P < .001), and type 1 curves, with pleomorphic adenomas (P < .001). Semiquantitative analysis for malignancy prediction yielded an area under the receiver operating characteristic curve of 0.85 (95% CI, 0.73-0.99). Combining time-to-maximum and ADC predicts pleomorphic adenoma better than either metric alone (P < .001). CONCLUSIONS: Golden-angle radial sparse parallel MR imaging allows high spatial and temporal resolution permeability characterization of parotid neoplasms, with a high negative predictive value for malignancy prediction. Combining time-to-maximum and ADC improves pleomorphic adenoma prediction compared with either metric alone.

Role of High-Resolution Dynamic Contrast-Enhanced MRI with Golden-Angle Radial Sparse Parallel Reconstruction to Identify the Normal Pituitary Gland in Patients with Macroadenomas.

BACKGROUND AND PURPOSE: Preoperative localization of the pituitary gland with imaging in patients with macroadenomas has been inadequately explored. The pituitary gland enhancing more avidly than a macroadenoma has been described in the literature. Taking advantage of this differential enhancement pattern, our aim was to evaluate the role of high-resolution dynamic MR imaging with golden-angle radial sparse parallel reconstruction in localizing the pituitary gland in patients undergoing trans-sphenoidal resection of a macroadenoma. MATERIALS AND METHODS: A retrospective study was performed in 17 patients who underwent trans-sphenoidal surgery for pituitary macroadenoma. Radial volumetric interpolated brain examination sequences with golden-angle radial sparse parallel technique were obtained. Using an ROI-based method to obtain signal-time curves and permeability measures, 3 separate readers identified the normal pituitary gland distinct from the macroadenoma. The readers' localizations were then compared with the intraoperative location of the gland. Statistical analyses were performed to assess the interobserver agreement and correlation with operative findings. RESULTS: The normal pituitary gland was found to have steeper enhancement-time curves as well as higher peak enhancement values compared with the macroadenoma (P < .001). Interobserver agreement was almost perfect in all 3 planes (κ = 0.89). In the 14 cases in which the gland was clearly identified intraoperatively, the correlation between the readers' localization and the true location derived from surgery was also nearly perfect (κ = 0.95). CONCLUSIONS: This study confirms our ability to consistently and accurately identify the normal pituitary gland in patients with macroadenomas with the golden-angle radial sparse parallel technique with quantitative permeability measurements and enhancement-time curves.

High-Resolution DCE-MRI of the Pituitary Gland Using Radial k-Space Acquisition with Compressed Sensing Reconstruction.

BACKGROUND AND PURPOSE: The pituitary gland is located outside of the blood-brain barrier. Dynamic T1 weighted contrast enhanced sequence is considered to be the gold standard to evaluate this region. However, it does not allow assessment of intrinsic permeability properties of the gland. Our aim was to demonstrate the utility of radial volumetric interpolated brain examination with the golden-angle radial sparse parallel technique to evaluate permeability characteristics of the individual components (anterior and posterior gland and the median eminence) of the pituitary gland and areas of differential enhancement and to optimize the study acquisition time. MATERIALS AND METHODS: A retrospective study was performed in 52 patients (group 1, 25 patients with normal pituitary glands; and group 2, 27 patients with a known diagnosis of microadenoma). Radial volumetric interpolated brain examination sequences with golden-angle radial sparse parallel technique were evaluated with an ROI-based method to obtain signal-time curves and permeability measures of individual normal structures within the pituitary gland and areas of differential enhancement. Statistical analyses were performed to assess differences in the permeability parameters of these individual regions and optimize the study acquisition time. RESULTS: Signal-time curves from the posterior pituitary gland and median eminence demonstrated a faster wash-in and time of maximum enhancement with a lower peak of enhancement compared with the anterior pituitary gland (P < .005). Time-optimization analysis demonstrated that 120 seconds is ideal for dynamic pituitary gland evaluation. In the absence of a clinical history, differences in the signal-time curves allow easy distinction between a simple cyst and a microadenoma. CONCLUSIONS: This retrospective study confirms the ability of the golden-angle radial sparse parallel technique to evaluate the permeability characteristics of the pituitary gland and establishes 120 seconds as the ideal acquisition time for dynamic pituitary gland imaging.

PI3K regulation of the SKP-2/p27 axis through mTORC2.

The cyclin-dependent kinase inhibitor p27 is a key regulator of cell-cycle progression. Its expression and localization are altered in several types of malignancies, which has prognostic significance in cancers such as renal cell carcinoma (RCC). S-phase kinase-associated protein 2 (SKP-2) is an F-box protein that is part of the SKP-1/Cul1/F-box ubiquitin ligase complex that targets nuclear p27 among many other cell-cycle proteins for proteosomal degradation. Its overexpression has been observed in several tumor types. Signaling by phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) has previously been shown to regulate the SKP-2/p27 axis. Recent evidence suggests that PI3K signaling may activate mammalian target of rapamycin complex 2 (mTORC2) activity. As PI3K signaling is known to regulate SKP-2 and p27, we sought to determine whether these effects were mediated by mTORC2. Here we provide additional genetic evidence that PI3K signaling activates mTORC2 kinase activity. We also demonstrate a novel role for mTORC2 in the modulation of nuclear p27 levels. In particular, mTORC2 signaling promotes the reduction of nuclear p27 protein levels through the increased protein expression of SKP-2. These are the first data to demonstrate a role for mTOR in the regulation of SKP-2. In concordance with these findings, mTORC2 activity promotes cell proliferation of RCC cells at the G1-S interphase of the cell cycle. Collectively, these data implicate mTORC2 signaling in the regulation of the SKP-2/p27 axis, a signaling node commonly altered in cancer.

Stabilization of HIF-2α through redox regulation of mTORC2 activation and initiation of mRNA translation.

Hypoxia inducible factor-2α (HIF-2α) has a critical role in renal tumorigenesis. HIF-2α is stabilized in von Hippel-Lindau (VHL)-deficient renal cell carcinoma through mechanisms that require ongoing mRNA translation. Mammalian target of rapamycin (mTOR) functions in two distinct complexes: Raptor-associated mTORC1 and Rictor-associated mTORC2. Rictor-associated mTORC2 complex has been linked to maintaining HIF-2α protein in the absence of VHL; however, the mechanisms remain to be elucidated. Although Raptor-associated mTORC1 is a known key upstream regulator of mRNA translation, initiation and elongation, the role of mTORC2 in regulating mRNA translation is not clear. Complex assembly of the mRNA cap protein, eukaryotic translation initiation factor 4 (eIF4)E, with activators (eIF4 gamma (eIF4G)) and inhibitors (eIF4E-binding protein 1 (4E-BP1)) are rate-limiting determinants of mRNA translation. Our laboratory has previously demonstrated that reactive oxygen species, mediated by p22(phox)-based Nox oxidases, are enhanced in VHL-deficient cells and have a role in the activation of Akt on S473, a site phosphorylated by the mTORC2 complex. In this study, we examined the role of Rictor-dependent regulation of HIF-2α through eIF4E-dependent mRNA translation and examined the effects of p22(phox)-based Nox oxidases on TORC2 regulation. We demonstrate for the first time that mTORC2 complex stability and activation is redox sensitive, and further defined a novel role for p22(phox)-based Nox oxidases in eIF4E-dependent mRNA translation through mTORC2. Furthermore, we provide the first evidence that silencing of p22(phox) reduces HIF-2α-dependent gene targeting in vitro and tumor formation in vivo. The clinical relevance of these studies is demonstrated.

Clinical evaluation of a viscoelastic gel for reduction of adhesions following gynaecological surgery by laparoscopy in Europe.

BACKGROUND: Commonly used adhesion prevention devices either cannot be applied or are difficult to use via laparoscopy. A viscoelastic gel was developed specifically for adhesion prophylaxis during minimally invasive surgery. METHODS: Randomized, third party-blinded, parallel-group design conducted at four centres. Patients (18-46 years old) underwent laparoscopic surgery with second look 6-10 weeks later. Viscoelastic gel coated adnexa and adjacent tissues. Blinded reviews of videotapes were quantified by American Fertility Society (AFS) adhesion scores. RESULTS: In 25 treatment patients, surgery was performed on 45 adnexa. Coverage of surgical sites at risk for adhesions was typically accomplished with approximately 15 ml of viscoelastic gel which was delivered in approximately 90 s. In 24 control patients, surgery alone was performed on 41 adnexa. Treated adnexa showed a decrease in AFS score (11.9-9.1). In contrast, control adnexa showed an increase in AFS score (8.8-15.8). This difference in second-look AFS scores (42% reduction) is significant (P<0.01). Ninety-three per cent of treated adnexa did not have a worse adhesion score in contrast to 56% of control adnexa. Combining scores into prognostic categories also show significant treatment effect of the viscoelastic gel (P<0.01). CONCLUSION: Viscoelastic gel was easy to use via laparoscopy and produced significant reduction in adnexal adhesions. It provides benefits to patients undergoing gynaecological surgery.

The human papillomavirus (HPV) 16 E6 oncoprotein leads to an increase in gene expression of the angiogenic switch molecule FGF-BP in non-immortalized human keratinocytes.

Fibroblast growth factor binding protein (FGF-BP) is a secreted protein that binds FGF-1 and FGF-2 and is involved in mobilization and activation of FGFs from the extracellular matrix. FGF-BP overexpression as well as ribozyme-mediated reduction of endogenous FGF-BP revealed that FGF-BP can be rate-limiting for tumor growth and angiogenesis. Recent studies showed that FGF-BP expression is up-regulated during early phases of tumorigenesis, indicating that the role of FGF-BP in angiogenesis is a critical early step in the development and progression of tumors. Human papillomavirus type 16 (HPV 16) is highly associated with the development of anogenital cancers. Here we demonstrate that the stable expression of the E6 oncogene of HPV 16 leads to an activation of the FGF-BP promoter in primary human foreskin keratinocytes (one of the natural host cells of these viruses). This is associated with an increase in the steady state levels of FGF-BP mRNA and FGF-BP protein in cells stably expressing E6. Transient E6 expression revealed that the observed activation of the FGF-BP promoter by the viral oncogene is an early process which is independent from immortalization/transformation events in the cells.

In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing müllerian system.

Diethylstilbestrol (DES) was widely used to treat pregnant women through 1971. The reproductive tracts of their female offspring exposed to DES in utero are characterized by anatomic abnormalities. Here we show that DES administered to mice in utero produces changes in the expression pattern of several Hox genes that are involved in patterning of the reproductive tract. DES produces posterior shifts in Hox gene expression and homeotic anterior transformations of the reproductive tract. In human uterine or cervical cell cultures, DES induces HOXA9 or HOXA10 gene expression, respectively, to levels approximately twofold that induced by estradiol. The DES-induced expression is not inhibited by cyclohexamide. Estrogens are novel morphogens that directly regulate the expression pattern of posterior Hox genes in a manner analogous to retinoic acid regulation of anterior Hox genes. Alterations in HOX gene expression are a molecular mechanism by which DES affects reproductive tract development. Changes in Hox gene expression are a potential marker for the effects of in utero drug use that may become apparent only at late stages of development.