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The detection of the Epoch of Reionization (EoR) delay power spectrum using a 'foreground avoidance method' highly depends on the instrument chromaticity. The systematic effects induced by the radio telescope spread the foreground signal in the delay domain, which contaminates the EoR window theoretically observable. Applied to the Hydrogen Epoch of Reionization Array (HERA), this paper combines detailed electromagnetic and electrical simulations in order to model the chromatic effects of the instrument, and quantify its frequency and time responses. In particular, the effects of the analogue receiver, transmission cables, and mutual coupling are included. These simulations are able to accurately predict the intensity of the reflections occurring in the 150-m cable which links the antenna to the backend. They also show that electromagnetic waves can propagate from one dish to another one through large sections of the array due to mutual coupling. The simulated system time response is attenuated by a factor 104 after a characteristic delay which depends on the size of the array and on the antenna position. Ultimately, the system response is attenuated by a factor 105 after 1400 ns because of the reflections in the cable, which corresponds to characterizable ka-modes above 0.7 $h\,\,\rm {Mpc}^{-1}$ at 150 MHz. Thus, this new study shows that the detection of the EoR signal with HERA Phase I will be more challenging than expected. On the other hand, it improves our understanding of the telescope, which is essential to mitigate the instrument chromaticity.

Characterizing the epoch of reionization (EoR) at z 6 via the redshifted 21 cm line of neutral Hydrogen (H i) is critical to modern astrophysics and cosmology, and thus a key science goal of many current and planned low-frequency radio telescopes. The primary challenge to detecting this signal is the overwhelmingly bright foreground emission at these frequencies, placing stringent requirements on the knowledge of the instruments and inaccuracies in analyses. Results from these experiments have largely been limited not by thermal sensitivity but by systematics, particularly caused by the inability to calibrate the instrument to high accuracy. The interferometric bispectrum phase is immune to antenna-based calibration and errors therein, and presents an independent alternative to detect the EoR H i fluctuations while largely avoiding calibration systematics. Here, we provide a demonstration of this technique on a subset of data from the Hydrogen Epoch of Reionization Array (HERA) to place approximate constraints on the brightness temperature of the intergalactic medium (IGM). From this limited data, at z=7.7 we infer "1σ"upper limits on the IGM brightness temperature to be ≤ 316 "pseudo"mK at κ =0.33 "pseudo"h Mpc-1 (data-limited) and ≤ 1000 "pseudo"mK at κ =0.875 "pseudo"h Mpc-1 (noise-limited). The "pseudo"units denote only an approximate and not an exact correspondence to the actual distance scales and brightness temperatures. By propagating models in parallel to the data analysis, we confirm that the dynamic range required to separate the cosmic H i signal from the foregrounds is similar to that in standard approaches, and the power spectrum of the bispectrum phase is still data-limited (at 106 dynamic range) indicating scope for further improvement in sensitivity as the array build-out continues.

The key challenge in the observation of the redshifted 21-cm signal from cosmic reionization is its separation from the much brighter foreground emission. Such separation relies on the different spectral properties of the two components, although, in real life, the foreground intrinsic spectrum is often corrupted by the instrumental response, inducing systematic effects that can further jeopardize the measurement of the 21-cm signal. In this paper, we use Gaussian Process Regression to model both foreground emission and instrumental systematics in ∼2 h of data from the Hydrogen Epoch of Reionization Array. We find that a simple co-variance model with three components matches the data well, giving a residual power spectrum with white noise properties. These consist of an 'intrinsic' and instrumentally corrupted component with a coherence scale of 20 and 2.4 MHz, respectively (dominating the line-of-sight power spectrum over scales kâ ≤ 0.2 h cMpc-1) and a baseline-dependent periodic signal with a period of ∼1 MHz (dominating over kâ ∼0.4-0.8 h cMpc-1), which should be distinguishable from the 21-cm Epoch of Reionization signal whose typical coherence scale is ∼0.8 MHz.

In 21-cm cosmology, precision calibration is key to the separation of the neutral hydrogen signal from very bright but spectrally smooth astrophysical foregrounds. The Hydrogen Epoch of Reionization Array (HERA), an interferometer specialized for 21-cm cosmology and now under construction in South Africa, was designed to be largely calibrated using the self-consistency of repeated measurements of the same interferometric modes. This technique, known as redundant-baseline calibration resolves most of the internal degrees of freedom in the calibration problem. It assumes, however, on antenna elements with identical primary beams placed precisely on a redundant grid. In this work, we review the detailed implementation of the algorithms enabling redundant-baseline calibration and report results with HERA data.We quantify the effects of real-world non-redundancy and how they compare to the idealized scenario in which redundant measurements differ only in their noise realizations. Finally, we study how non-redundancy can produce spurious temporal structure in our calibration solutions-both in data and in simulations-and present strategies for mitigating that structure.

Radio frequency interference (RFI) is an ever-present limiting factor among radio telescopes even in the most remote observing locations. When looking to retain the maximum amount of sensitivity and reduce contamination for Epoch of Reionization studies, the identification and removal of RFI is especially important. In addition to improved RFI identification, we must also take into account computational efficiency of the RFI-Identification algorithm as radio interferometer arrays such as the Hydrogen Epoch of Reionization Array (HERA) grow larger in number of receivers. To address this, we present a deep fully convolutional neural network (DFCN) that is comprehensive in its use of interferometric data, where both amplitude and phase information are used jointly for identifying RFI. We train the network using simulated HERA visibilities containing mock RFI, yielding a known ‘ground truth’ data set for evaluating the accuracy of various RFI algorithms. Evaluation of the DFCN model is performed on observations from the 67 dish build-out, HERA-67, and achieves a data throughput of 1.6 × 105 HERA time-ordered 1024 channelled visibilities per hour per GPU. We determine that relative to an amplitude only network including visibility phase adds important adjacent time–frequency context which increases discrimination between RFI and non-RFI. The inclusion of phase when predicting achieves a recall of 0.81, precision of 0.58, and F2 score of 0.75 as applied to our HERA-67 observations.

Foreground power dominates the measurements of interferometers that seek a statistical detection of highly-redshifted H i emission from the Epoch of Reionization (EoR). The chromaticity of the instrument creates a boundary in the Fourier transform of frequency (proportional to k ∥) between spectrally smooth emission, characteristic of the strong synchrotron foreground (the "wedge"), and the spectrally structured emission from H i in the EoR (the "EoR window"). Faraday rotation can inject spectral structure into otherwise smooth polarized foreground emission, which through instrument effects or miscalibration could possibly pollute the EoR window. For instruments pursuing a "foreground avoidance" strategy of simply measuring in the EoR window, and not attempting to model and remove foregrounds, as is the plan for the first stage of the Hydrogen Epoch of Reionization Array (HERA), characterizing the intrinsic instrument polarization response is particularly important. Using data from the HERA 19-element commissioning array, we investigate the polarization response of this new instrument in the power-spectrum domain. We perform a simple image-based calibration based on the unpolarized diffuse emission of the Global Sky Model, and show that it achieves qualitative redundancy between the nominally redundant baselines of the array and reasonable amplitude accuracy. We construct power spectra of all fully polarized coherencies in all pseudo-Stokes parameters, and discuss the achieved isolation of foreground power due to the intrinsic spectral smoothness of the foregrounds, the instrument chromaticity, and the calibration. We compare to simulations based on an unpolarized diffuse sky model and detailed electromagnetic simulations of the dish and feed, confirming that in Stokes I, the calibration does not add significant spectral structure beyond that expected from the interferometer array configuration and the modeled primary beam response. Furthermore, this calibration is stable over the 8 days of observations considered. Excess power is seen in the power spectra of the linear polarization Stokes parameters, which is not easily attributable to leakage via the primary beam, and results from some combination of residual calibration errors and actual polarized emission. Stokes V is found to be highly discrepant from the expectation of zero power, strongly pointing to the need for more accurate polarized calibration.

21 cm cosmology is a promising new probe of the evolution of visible matter in our universe, especially during the poorly constrained Cosmic Dawn and Epoch of Reionization. However, in order to separate the 21 cm signal from bright astrophysical foregrounds, we need an exquisite understanding of our telescopes so as to avoid adding spectral structure to spectrally smooth foregrounds. One powerful calibration method relies on repeated simultaneous measurements of the same interferometric baseline to solve for the sky signal and for instrumental parameters simultaneously. However, certain degrees of freedom are not constrained by asserting internal consistency between redundant measurements. In this paper, we review the origin of these degeneracies of redundant-baseline calibration and demonstrate how they can source unwanted spectral structure in our measurement and show how to eliminate that additional, artificial structure. We also generalize redundant calibration to dual-polarization instruments, derive the degeneracy structure, and explore the unique challenges to calibration and preserving spectral smoothness presented by a polarized measurement.

Spectral structures due to the instrument response is the current limiting factor for the experiments attempting to detect the redshifted 21 cm signal from the Epoch of Reionization (EoR). Recent advances in the delay spectrum methodology for measuring the redshifted 21 cm EoR power spectrum brought new attention to the impact of an antenna’s frequency response on the viability of making this challenging measurement. The delay spectrum methodology provides a somewhat straightforward relationship between the time-domain response of an instrument that can be directly measured and the power spectrum modes accessible to a 21 cm EoR experiment. In this paper, we derive the explicit relationship between antenna reflection coefficient (S11) measurements made by a Vector Network Analyzer (VNA) and the extent of additional foreground contaminations in delay space. In the light of this mathematical framework, we examine the chromaticity of a prototype antenna element that will constitute the Hydrogen Epoch of Reionization Array (HERA) between 100 and 200 MHz. These reflectometry measurements exhibit additional structures relative to electromagnetic simulations, but we find that even without any further design improvement, such an antenna element will support measuring spatial k modes with line-of-sight components of k∥ > 0.2h Mpc− 1. We also find that when combined with the powerful inverse covariance weighting method used in optimal quadratic estimation of redshifted 21 cm power spectra the HERA prototype elements can successfully measure the power spectrum at spatial modes as low as k∥ > 0.1h Mpc− 1. This work represents a major step toward understanding the HERA antenna element and highlights a straightforward method for characterizing instrument response for future experiments designed to detect the 21 cm EoR power spectrum.

In order to study the "Cosmic Dawn" and the Epoch of Reionization with 21 cm tomography, we need to statistically separate the cosmological signal from foregrounds known to be orders of magnitude brighter. Over the last few years, we have learned much about the role our telescopes play in creating a putatively foreground-free region called the "EoR window." In this work, we examine how an interferometer's effects can be taken into account in a way that allows for the rigorous estimation of 21 cm power spectra from interferometric maps while mitigating foreground contamination and thus increasing sensitivity. This requires a precise understanding of the statistical relationship between the maps we make and the underlying true sky. While some of these calculations would be computationally infeasible if performed exactly, we explore several well-controlled approximations that make mapmaking and the calculation of map statistics much faster, especially for compact and highly redundant interferometers designed specifically for 21 cm cosmology. We demonstrate the utility of these methods and the parametrized trade-offs between accuracy and speed using one such telescope, the upcoming Hydrogen Epoch of Reionization Array, as a case study.

The Ca2+ antagonists are a novel group of drugs useful in management of a variety of cardiac disorders. They differ from one another in terms of their chemistry, tissue specificity and selectivity. As a group, however, they share the common property of slowing Ca2+ entry through voltage-activated, ion-selective channels. Some of them exhibit other properties, including that of interfering with Na+ transport. At least one of them, diltiazem, has an intracellular action. Specific high and low affinity binding sites have been identified for two of the major groups of Ca2+-antagonists, with the binding sites for verapamil and its derivatives being distinct from those which can be occupied by the dihydropyridines. The number (Bmax) and affinity (KD) of these binding sites changes under certain pathological conditions-including a reduction in ischaemia and in spontaneous hypertension, an increase in the latter, at present, only demonstrated for the dihydropyridine binding sites. The sensitivity of a particular tissue to these drugs will depend upon a number of factors including the number of binding sites that are present, the contribution made by the Ca2+ entering through the voltage-activated channels to the functioning of the tissue, and properties which are peculiar to a particular type of Ca2+ antagonist, for example, whether, as in the case of verapamil, they exhibit use-dependence. [ABSTRACT FROM AUTHOR]

Background: Screening for carcinoid heart disease (CHD), has historically lacked consensus expert guidelines. In 2017, the North American Neuroendocrine Tumor Society (NANETS) released expert recommendations for CHD screening among NET patients to improve CHD detection. The objective of this study is to evaluate CHD screening trends and utility of screening guidelines over more than two decades at a single tertiary care center., Materials and Methods: Patients with NETs referred for abdominal surgical evaluation at a single tertiary care center were included, 300 patients from 1999 to 2018 and 34 patients from 2021 to 2022. Lab values for the following NANETS-proposed criteria at any point during their treatments were recorded: NETs with liver metastasis, blood serotonin >5 times upper limit of normal (>1000 ng/mL), NT-ProBNP >260 pg/mL and clinical features suggestive of CHD., Results: 85 % (285/334) of patients included in this study met one or more expert-recommended CHD screening criteria. However, 40 % (132/285) of patients meeting one or more criteria received CHD screening via echocardiogram at some point following NET diagnosis. While rates of screening for patients increased from the first decade to the second decade (32 % vs 40.6 %), the rates were much higher after guideline publication (70 %, 24/34). Furthermore, patients meeting multiple screening criteria were more likely to have evidence of structural valve disease., Conclusions: Results of this study suggest that utilization of these four expert-recommended screening criteria have greatly increased rates of CHD screening via echocardiogram and could assist in improving early CHD detection, especially for patients meeting multiple criteria., (© 2024 The Author(s).)

Targeted radionuclide therapies (TRT) using 131 I-metaiodobenzylguanidine ( 131 I-MIBG) and peptide receptor radionuclide therapy ( 177 Lu or 90 Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity- 131 I-MIBG therapy was approved by the FDA and both 177 Lu-DOTATATE and 131 I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs., (©2021 American Association for Cancer Research.)

Pheochromocytomas and paragangliomas (PPG) are rare cancers arising from the adrenal medulla (pheochromocytoma) or autonomic ganglia (paraganglioma). They have highly variable biological behavior. Most PPG express high-affinity norepinephrine transporters, allowing active uptake of the norepinephrine analog, 131 iodine-metaiodobenzylguanidine ( 131 I-MIBG). Low-specific-activity forms of 131 I-MIBG have been used since 1983 for therapy of PPG. High-specific-activity  131 I-MIBG therapy improves hypertension management, induces partial radiological response or stable disease, decreases biochemical markers of disease activity and is well tolerated by patients. This drug, approved in the USA in July 2018, is the first approved agent for patients with unresectable, locally advanced or metastatic PPG and imaging evidence of metaiodobenzylguanidine uptake, who require systemic anticancer therapy.

Purpose: Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the past decades, most patients will die of metastatic disease. New systemic therapies are needed., Experimental Design: Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity pathway analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1)., Results: A total of 902 genes were differentially expressed in pNET metastases compared with primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, protein kinase C, NF-kB, cyclin-dependent kinase, and histone deacetylase. Inhibitors of MEK and TOP2A were consistently the most active compounds., Conclusions: We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for patients with pNETs., (©2020 American Association for Cancer Research.)

Background: Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome., Subjects, Materials, and Methods: Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated., Results: Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4., Conclusion: Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome., Implications for Practice: Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Patients with metastatic or unresectable (advanced) pheochromocytoma and paraganglioma (PPGL) have poor prognoses and few treatment options. This multicenter, phase 2 trial evaluated the efficacy and safety of high-specific-activity 131 I-meta-iodobenzylguanidine (HSA 131 I-MIBG) in patients with advanced PPGL. Methods: In this open-label, single-arm study, 81 PPGL patients were screened for enrollment, and 74 received a treatment-planning dose of HSA 131 I-MIBG. Of these patients, 68 received at least 1 therapeutic dose (∼18.5 GBq) of HSA 131 I-MIBG intravenously. The primary endpoint was the proportion of patients with at least a 50% reduction in baseline antihypertensive medication use lasting at least 6 mo. Secondary endpoints included objective tumor response as assessed by Response Evaluation Criteria in Solid Tumors version 1.0, biochemical tumor marker response, overall survival, and safety. Results: Of the 68 patients who received at least 1 therapeutic dose of HSA 131 I-MIBG, 17 (25%; 95% confidence interval, 16%-37%) had a durable reduction in baseline antihypertensive medication use. Among 64 patients with evaluable disease, 59 (92%) had a partial response or stable disease as the best objective response within 12 mo. Decreases in elevated (≥1.5 times the upper limit of normal at baseline) serum chromogranin levels were observed, with confirmed complete and partial responses 12 mo after treatment in 19 of 28 patients (68%). The median overall survival was 36.7 mo (95% confidence interval, 29.9-49.1 mo). The most common treatment-emergent adverse events were nausea, myelosuppression, and fatigue. No patients had drug-related acute hypertensive events during or after the administration of HSA 131 I-MIBG. Conclusion: HSA 131 I-MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Pretherapy PET with 86 Y-DOTATOC is considered the ideal dosimetry protocol for 90 Y-DOTATOC therapy; however, its cost, limited availability, and need for infusion of amino acids to mimic the therapy administration limit its use in the clinical setting. The goal of this study was to develop a dosimetric method for 90 Y-DOTATOC using 90 Y-DOTATOC PET/CT and bremsstrahlung SPECT/CT and to determine whether dosimetry-based administered activities differ significantly from standard administered activities. Methods: This was a prospective phase 2 trial of 90 Y-DOTATOC therapy in patients with somatostatin receptor-positive tumors. 90 Y-DOTATOC was given in 3 cycles 6-8 wk apart. In the first cycle of therapy, adults received 4.4 GBq and children received 1.85 GBq/m 2 ; the subsequent administered activities were adjusted according to the dosimetry of the preceding cycle so as not to exceed a total kidney dose of 23 Gy and bone marrow dose of 2 Gy. The radiation dose to the kidneys was determined from serial imaging sessions consisting of time-of-flight 90 Y-DOTATOC PET/CT at 5 h after therapy and 90 Y-DOTATOC bremsstrahlung SPECT/CT at 6, 24, 48, and 72 h. The PET/CT data were used to measure the absolute concentration of 90 Y-DOTATOC and to calibrate the bremsstrahlung SPECT kidney clearance data. The radiation dose to the kidneys was determined by multiplying the time-integrated activity (from the fitted biexponential curve of renal clearance of 90 Y-DOTATOC) with the energy emitted per decay, divided by the mass of the kidneys. Results: The radiation dose to the kidneys per cycle of 90 Y-DOTATOC therapy was highly variable among patients, ranging from 0.32 to 3.0 mGy/MBq. In 17 (85%) of the 20 adult patients who received the second and the third treatment cycles of 90 Y-DOTATOC, the administered activity was modified by at least 20% from the starting administered activity. Conclusion: Renal dosimetry of 90 Y-DOTATOC is feasible using 90 Y-DOTATOC time-of-flight PET/CT and bremsstrahlung SPECT/CT and has a significant impact on the administered activity in treatment cycles., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Carcinoid syndrome (CS), characterized by diarrhea and flushing, is present in 20% of patients with neuroendocrine tumors at diagnosis and becomes more frequent with progression. The diarrhea of CS is caused mainly by tumoral secretion of serotonin. It may not be fully controlled by somatostatin analogs, the currently indicated drugs for symptomatic relief. Telotristat ethyl is a novel inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis. Administration of the drug decreases diarrhea in patients with CS. Telotristat ethyl was approved in February 2017 (USA) and September 2017 (European Commission) for the treatment of CS diarrhea in adults inadequately controlled by somatostatin analog alone. This drug is expected to greatly improve the health and quality of life of patients with CS diarrhea.

Localization of the site of the unknown primary tumor is critical for surgical treatment of patients presenting with neuroendocrine tumor (NET) with metastases. Methods: Forty patients with metastatic NET and unknown primary site underwent 68 Ga-DOTATOC PET/CT in a single-site prospective study. The 68 Ga-DOTATOC PET/CT was considered true-positive if the positive primary site was confirmed by histology or follow-up imaging. The scan was considered false-positive if no primary lesion was found corresponding to the 68 Ga-DOTATOC-positive site. All negative scans for primary tumor were considered false-negative. A scan was classified unconfirmed if 68 Ga-DOTATOC PET/CT suggested a primary, however, no histology was obtained and imaging follow-up was not confirmatory. Results: The true-positive, false-positive, false-negative, and unconfirmed rates for unknown primary tumor were 38%, 7%, 50%, and 5%, respectively. Conclusion: 68 Ga-DOTATOC PET/CT is an effective modality in the localization of unknown primary in patients with metastatic NET., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Aim: To evaluate the discrepancies between the diameter of the canal and the first file to bind at the working length, before and after preflaring in teeth with apical curvatures., Materials and Methods: Twenty teeth with apical curvatures were selected for the study. Following access, the patency file was fixed at the working length, and the apices were ground perpendicular to the canal at this level. Diameters of canal and the first file to bind at the working length were observed for each tooth, both before and after preflaring, under stereomicroscope at 30X magnification., Results: ANOVA and post hoc Bonferroni tests showed significant differences in both groups regarding anatomical diameter at working length and the first file to bind. The area of contact of the file at apical region remained the same in both groups., Conclusion: Using the first file to bind for gauging the diameter of the apical canal was found to be an unreliable method in teeth with apical curvatures, even after preflaring.

Dehydroepiandrosterone (DHEA) activates a plasma membrane receptor on vascular endothelial cells and phosphorylates ERK 1/2. We hypothesize that ERK1/2-dependent vascular endothelial proliferation underlies part of the beneficial vascular effect of DHEA. DHEA (0.1-10 nm) activated ERK1/2 in bovine aortic endothelial cells (BAECs) by 15 min, causing nuclear translocation of phosphorylated ERK1/2 and phosphorylation of nuclear p90 ribosomal S6 kinase. ERK1/2 phosphorylation was dependent on plasma membrane-initiated activation of Gi/o proteins and the upstream MAPK kinase because the effect was seen with albumin-conjugated DHEA and was blocked by pertussis toxin or PD098059. A 15-min incubation of BAECs with 1 nm DHEA (or albumin-conjugated DHEA) increased endothelial proliferation by 30% at 24 h. This effect was not altered by inhibition of estrogen or androgen receptors or nitric oxide production. There was a similar effect of DHEA to increase endothelial migration. DHEA also increased the formation of primitive capillary tubes of BAECs in vitro in solubilized basement membrane. These rapid DHEA-induced effects were reversed by the inhibition of either Gi/o-proteins or ERK1/2. Additionally, DHEA enhanced angiogenesis in vivo in a chick embryo chorioallantoic membrane assay. These findings indicate that exposure to DHEA, at concentrations found in human blood, causes vascular endothelial proliferation by a plasma membrane-initiated activity that is Gi/o and ERK1/2 dependent. These data, along with previous findings, define an important vascular endothelial cell signaling pathway that is activated by DHEA and suggest that this steroid may play a role in vascular function.

The adrenal steroid dehydroepiandrosterone (DHEA) may improve vascular function, but the mechanism is unclear. In the present study, we show that DHEA significantly increased cell viability, reduced caspase-3 activity, and protected both bovine and human vascular endothelial cells against serum deprivation-induced apoptosis. This effect was dose dependent and maximal at physiological concentrations (0.1-10 nM). DHEA stimulation of bovine aortic endothelial cells resulted in rapid and dose-dependent phosphorylation of Akt, which was blocked by LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), the upstream kinase of Akt. Accordingly, inhibition of PI3K or transfection of the cells with dominant-negative Akt ablated the antiapoptotic effect of DHEA. The induced Akt phosphorylation and subsequent cytoprotective effect of DHEA were dependent on activation of Galphai proteins, but were estrogen receptor independent, because these effects were blocked by pertussis toxin but not by the estrogen receptor inhibitor ICI182,780 or the aromatase inhibitor aminoglutethimide. Finally, DHEA enhanced antiapoptotic Bcl-2 protein expression, its promoter activity, and gene transcription attributable to the activation of the PI3K/Akt pathway. Neutralization of Bcl-2 by antibody transfection significantly decreased the antiapoptotic effect of DHEA. These findings provide the first evidence that DHEA acts as a survival factor for endothelial cells by triggering the Galphai-PI3K/Akt-Bcl-2 pathway to protect cells against apoptosis. This may represent an important mechanism underlying the vascular protective effect of DHEA.