Abstract Purpose To explore modified parameters for The ACR Thyroid Imaging Reporting and Data System (TI-RADS) of contralateral nodules based on preoperative ultrasound features of suspected-lobe papillary thyroid carcinoma (PTC), to assist managing bilateral PTC. Methods 389 consecutive PTC patients (272 in training set and 117 in validation set) who underwent total thyroidectomy in our center were retrospectively analyzed from March 2020 to March 2022. According to postoperative pathological data, the patients were divided into unilateral and bilateral PTC group. The clinicopathological features and sonographic characteristics of suspected nodules were compared between the two groups and further ultrasonic characteristics of underestimated nodules were analyzed. Results Patients with BMI ≥ 25 kg/m2, multifocality in suspected-lobe, isthmus nodule with TI-RADS classification > 3 tended to have bilateral PTC (P < 0.001, P < 0.001, and P = 0.03, respectively). After modifying ACR TI-RADS classification of contralateral nodules using the above three parameters, AUC for diagnosing contralateral lesions increased from 0.79 (95%CI: 0.74–0.84) to 0.83 (0.78–0.87) in training set. Missed-diagnosis rate of contralateral PTCs were both decreased in training set [21.1% (28/133) to 4.5% (6/133)] and validation set [11.4% (8/70) to 2.9% (2/70)]. In addition, the presence of cystic components and halo sign in contralateral nodules tend to be underestimated by ultrasound preoperatively, with underestimation rates of 100% (6/6) and 73.3% (11/15), respectively. Conclusion The modified ACR TI-RADS classification based on suspected-lobe may be an effective method for preoperative malignant risk stratification of contralateral nodules in patients with bilateral PTCs, which can avoid inadequate surgical extent.
Cyclic AMP synergizes strongly with glucocorticoids (GC) to induce apoptosis in normal or malignant lymphoid cells. We examined the individual roles that cAMP-dependent protein kinase (PKA) and Epac (exchange protein directly activated by cAMP), two intracellular cAMP receptors, play in this synergistic effect. Our studies demonstrate that PKA is responsible for the observed synergism with GC, whereas Epac exerts a weak antagonistic effect against GC-induced apoptosis. We find that endogenous PKA activity is higher in the GC-sensitive clone than in the GC-resistant clone. In the GC-sensitive clone, higher PKA activity is associated with lower Hedgehog (Hh) activity. Moreover, inhibition of Hh activity by Hh pathway-specific inhibitors leads to cell cycle arrest and apoptosis in CEM (human acute lymphoblastic leukemia, T lineage) cells, and the GC-sensitive clone is more sensitive to Hh inhibition. These results suggest that Hh activity is critical for leukemia cell growth and survival and that the level of Hh activity is in part responsible for the synergism between cAMP and GC.
The iv is a new hepatograp the authors, accordi of the reticulo-endo suspension of TABAChic agent, designed by ng to the phagocytosis thelial tissue. In this paper, we localized the distribution of sus-pension particles of [iasI]TABAC in rat liver by autoradiography. The silver grains produced by[125I]TABAC were concen-trated in and around Kupffer cells. This is a direct evidence to prove our design a successful one. The ratio of numbers of Ag grains with 2 doses (3.1)was smaller than that of 2 initial doses (4). The values of [125I]TABAC_positive Kupffer cells vs time (from 15 s t0 6 d) coincided with that of TABAC content in liver vs time deter-mined by a previous pharmacokinetic study.
In Brief Study Design. A new in vivo sheep model was developed that produced disc degeneration through the injection of 5-bromodeoxyuridine (BrdU) into the intervertebral disc. This process was studied using magnetic resonance imaging (MRI), radiography, CT/discogram, histology, and biochemistry. Objectives. To develop a sheep model of intervertebral disc degeneration that more faithfully mimics the pathologic hallmarks of human intervertebral disc degeneration. Summary of Background Data. Recent studies have shown age-related alterations in proteoglycan structure and organization in human intervertebral discs. An animal model that involves the use of age-related changes in disc cells can be beneficial over other more invasive degenerative models that involves directly damaging the matrix of disc tissue. Methods. Twelve sheep were injected with BrdU or vehicle (phosphate-buffered saline) into the central region of separate lumbar discs. Intact discs were used as controls. At the 2-, 6-, 10-, and 14-week time points, discs underwent MRI, radiography, histology, and biochemical analyses. A CT/discogram study was performed at the 14-week time point. Results. MRI demonstrated a progressive loss of T2-weighted signal intensity at BrdU-injected discs over the 14-week study period. Radiograph findings included osteophyte and disc space narrowing formed by 10 weeks post-BrdU treatment. CT discography demonstrated internal disc disruption in several BrdU-treated discs at the 14-week time point. Histology showed a progressive loss of the normal architecture and cell density of discs from the 2-week time point to the 14-week time point. A progressive loss of cell proliferation capacity, water content, and proteoglycans was also documented. Conclusions. BrdU injection into the central region of sheep discs resulted in degeneration of intervertebral discs. This progressive, degenerative process was confirmed using MRI, histology, and by observing changes in biochemistry. Degeneration occurred in a manner that was similar to that observed in human disc degeneration. Sheep underwent injection of BrdU into the central region of lumbar intervertebral discs using a CT-guided system. Discs underwent examination using MRI, radiography, CT/discography, histology, and biochemistry, identifying the formation of lumbar intervertebral disc degeneration.
Epac2, a guanine nucleotide exchange factor, regulates a wide variety of intracellular processes in response to second messenger cAMP. In this study, we have used peptide amide hydrogen/deuterium exchange mass spectrometry to probe the solution structural and conformational dynamics of full-length Epac2 in the presence and absence of cAMP. The results support a mechanism in which cAMP-induced Epac2 activation is mediated by a major hinge motion centered on the C terminus of the second cAMP binding domain. This conformational change realigns the regulatory components of Epac2 away from the catalytic core, making the later available for effector binding. Furthermore, the interface between the first and second cAMP binding domains is highly dynamic, providing an explanation of how cAMP gains access to the ligand binding sites that, in the crystal structure, are seen to be mutually occluded by the other cAMP binding domain. Moreover, cAMP also induces conformational changes at the ionic latch/hairpin structure, which is directly involved in RAP1 binding. These results suggest that in addition to relieving the steric hindrance imposed upon the catalytic lobe by the regulatory lobe, cAMP may also be an allosteric modulator directly affecting the interaction between Epac2 and RAP1. Finally, cAMP binding also induces significant conformational changes in the dishevelled/Egl/pleckstrin (DEP) domain, a conserved structural motif that, although missing from the active Epac2 crystal structure, is important for Epac subcellular targeting and in vivo functions.
cAMP-mediated signaling pathways regulate a multitude of important biological processes under both physiological and pathological conditions, including diabetes, heart failure and cancer. In eukaryotic cells, the effects of cAMP are mediated by two ubiquitously expressed intracellular cAMP receptors, the classic protein kinase A (PKA)/cAMP-dependent protein kinase and the recently discovered exchange protein directly activated by camp (Epac)/cAMP-regulated guanine nucleotide exchange factors. Like PKA, Epac contains an evolutionally conserved cAMP binding domain that acts as a molecular switch for sensing intracellular second messenger cAMP levels to control diverse biological functions. The existence of two families of cAMP effectors provides a mechanism for a more precise and integrated control of the cAMP signaling pathways in a spatial and temporal manner. Depending upon the specific cellular environments as well as their relative abundance, distribution and localization, Epac and PKA may act independently, converge synergistically or oppose each other in regulating a specific cellular function.
Cellular transformation is a complex process involving genetic alterations associated with multiple signaling pathways. Development of a transformation model using defined genetic elements has provided an opportunity to elucidate the role of oncogenes and tumor suppressor genes in the initiation and development of ovarian cancer. To study the cellular and molecular mechanisms of Ras-mediated oncogenic transformation of ovarian epithelial cells, we used a proteomic approach involving two-dimensional electrophoresis and mass spectrometry to profile two ovarian epithelial cell lines, one immortalized with SV40 T/t antigens and the human catalytic subunit of telomerase and the other transformed with an additional oncogenic ras(V12) allele. Of approximately 2200 observed protein spots, we have identified >30 protein targets that showed significant changes between the immortalized and transformed cell lines using peptide mass fingerprinting. Among these identified targets, one most notable group of proteins altered significantly consists of enzymes involved in cellular redox balance. Detailed analysis of these protein targets suggests that activation of Ras-signaling pathways increases the threshold of reactive oxidative species (ROS) tolerance by up-regulating the overall antioxidant capacity of cells, especially in mitochondria. This enhanced antioxidant capacity protects the transformed cells from high levels of ROS associated with the uncontrolled growth potential of tumor cells. It is conceivable that an enhanced antioxidation capability may constitute a common mechanism for tumor cells to evade apoptosis induced by oxidative stresses at high ROS levels.
Abstract Calcification within breast cancer is a diagnostically significant radiological feature that generally consists of hydroxylapatite. Samples from 30 cases of breast carcinoma with calcification were investigated using optical microscopy, energy-dispersive X-ray analysis, transmission-electron microscopy, Fourier-transform infrared spectroscopy, Raman spectroscopy, synchrotron radiation X-ray diffraction and X-ray fluorescence. Under optical microscopy, the calcifications were found to consist of either irregular aggregates with widths > 200 μm or spherical aggregates similar to psammoma bodies with an average diameter of 30 μm. Transmission-electron microscopy showed that short columnar or dumbbell-shaped crystals with widths of 10–15 nm and lengths of 20–50 nm were the most common morphology; spherical aggregates (~1 μm in diameter) with amorphous coatings of fibrous nanocrystals were also observed. Results indicated that hydroxylapatite was the dominant mineral phase in the calcifications, and both CO 3 2– and cation substitutions (Na, Mg, Zn, Fe, Sr, Cu and Mn) were present in the hydroxylapatite structure. Fourier-transform infrared spectra show peaks at 872 and 880 cm –1 indicating that CO 3 2– substituted both the OH – (A type) and PO 4 3– (B type) sites of hydroxylapatite, making it an A and B mixed type. The ratio of B- to A-type substitution was estimated in the range of 1.1–18.7 from the ratio of peak intensities ( I 872 / I 880 ), accompanied with CO 3 2– contents from 1.1% to 14.5%. Trace arsenic, detected in situ by synchrotron radiation X-ray fluorescence was found to be distributed uniformly in the calcifications in the form of AsO 4 3– substituting for PO 4 3– . It is therefore proposed that identifying these trace elements in breast cancer calcifications may be promising for future clinical diagnostics.
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