GH and prolactin (PRL) are structurally related hormones that exert important effects in disparate target tissues. Their receptors (GHR and PRLR) reside in the cytokine receptor superfamily and share signaling pathways. In humans, GH binds both GHR and PRLR, whereas PRL binds only PRLR. Both hormones and their receptors may be relevant in certain human and rodent cancers, including breast cancer. GH and PRL promote signaling in human T47D breast cancer cells that express both GHR and PRLR. Furthermore, GHR and PRLR associate in a fashion augmented acutely by GH, even though GH primarily activates PRLR, rather than GHR, in these cells. To better understand PRLR's impact, we examined the effects of PRLR knockdown on GHR availability and GH sensitivity in T47D cells. T47D-ShPRLR cells, in which PRLR expression was reduced by stable short hairpin RNA (shRNA) expression, were compared with T47D-SCR control cells. PRLR knockdown decreased the rate of GHR proteolytic turnover, yielding GHR protein increase and ensuing sensitization of these cells to GHR signaling events including phosphorylation of GHR, Janus kinase 2, and signal transducer and activator of transcription 5 (STAT5). Unlike in T47D-SCR cells, acute GH signaling in T47D-ShPRLR cells was not blocked by the PRLR antagonist G129R but was inhibited by the GHR-specific antagonist, anti-GHR(ext-mAb). Thus, GH's use of GHR rather than PRLR was manifested when PRLR was reduced. In contrast to acute effects, GH incubation for 2 h or longer yielded diminished STAT5 phosphorylation in T47D-ShPRLR cells compared with T47D-SCR, a finding perhaps explained by markedly greater GH-induced GHR down-regulation in cells with diminished PRLR. However, when stimulated with repeated 1-h pulses of GH separated by 3-h washout periods to more faithfully mimic physiological GH pulsatility, T47D-ShPRLR cells exhibited greater transactivation of a STAT5-responsive luciferase reporter than did T47D-SCR cells. Our data suggest that PRLR's presence meaningfully affects GHR use in breast cancer cells.
Objectives We evaluated telecytology rapid on-site evaluation (ROSE) for thyroid ultrasound-guided fine-needle aspiration. To the best of our knowledge, this study is the first case-control clinical trial of thyroid telecytology. Methods We introduced on-site ROSE in our institution’s thyroid clinic for 6 months, followed by telecytology for 12 months. Our institution’s ultrasound clinic, where ROSE is not provided, was used as a control group for each period. Results Both groups had similar initial unsatisfactory rates (thyroid clinic: 8.8%; ultrasound clinic: 8.0%) before the study began. The thyroid clinic’s unsatisfactory rate was significantly reduced to 1.6% after on-site ROSE (P = .001) and to 3.8% after telecytology ROSE (P = .010), with no significant difference between on-site and telecytology ROSE periods (P > .05). The ultrasound clinic’s unsatisfactory rate was unchanged for both periods. Concordance between telecytology ROSE and final adequacy was 97% (κ = 0.699). Conclusions Telecytology ROSE reduces unsatisfactory rates for ultrasound-guided fine-needle aspiration without compromising patient care.
Background: ACTH-producing pheochromocytomas (APP) are a rare cause of ectopic Cushing’s syndrome (CS), representing <6% of these cases. No guidelines exist on the management of these tumors. Clinical case: A 41-year-old woman presented to the ED with a 6-month history of newly-diagnosed T2DM and difficult-to-control hypertension. Three weeks prior to admission she developed fatigue, dyspnea on exertion, and generalized weakness particularly severe in the lower extremities (LE) limiting her ability to ambulate. She denied headaches, palpitations and diaphoresis. Initial vital signs included HR 111 beats/min and BP 217/112 mmHg. On physical exam she had classic findings of CS with severe LE weakness. Laboratory testing was consistent with ACTH-dependent CS (ACTH 463 pg/mL [0-45], cortisol 70.8 mcg/dL [3-23], potassium 2.7 mMol/L [3.1-5.1]). She failed both the low dose (1 mg) and high dose (8 mg) dexamethasone suppression tests. MRI of the pituitary gland ruled out a pituitary lesion. IPSS was not deemed necessary by Neurosurgery. CT abdomen showed a 4.2 cm right adrenal lesion and bilateral adrenal hyperplasia. This prompted workup for pheochromocytoma that revealed elevated plasma metanephrines (4.1 nMol/L, [<0.5]) and 24hr urine metanephrines (5329 mcg/day, [182-739]). A diagnosis of APP was entertained. Doxazosin 1 mg BID was added to her other antihypertensives with improvement in blood pressure. Ketoconazole 200 mg TID was started as a bridge for surgery. Patient underwent right unilateral adrenalectomy one month after initial presentation. ACTH and cortisol levels before surgery were 534 pg/mL and 87 mcg/dL, respectively, suggesting that ketoconazole was not effective. Both ACTH and cortisol levels decreased to 26 pg/mL and 14.4 mcg/dL, respectively, immediately after surgery. There was prompt subjective symptomatic improvement, including mild recovery of LE strength. Her blood pressure normalized and only spironolactone was continued. She was started on a prednisone taper. Pathology revealed a 4.2 pheochromocytoma and diffuse adrenocortical hyperplasia. Tumor cells stained positive for ACTH on immunohistochemistry. On follow up visit 2 months after surgery patient was feeling well and ambulating without difficulty. Labs were remarkable for normal plasma fractionated metanephrines, and A1c 5.1% on metformin alone (down from 4 medications on initial presentation). Conclusion: Diagnosis and management of APP can be challenging. Alpha-blockers should be started promptly. Definitive treatment with unilateral adrenalectomy is curative and has been recommended as the preferred approach.1 Ketoconazole may be used as bridge therapy for surgery, though some studies suggest its efficacy might be lower in ectopic CS.2 Response to other pharmacologic agents is largely unknown. References: 1. Surgery (1995) 118: 988-94 2. Clinical Endocrinology (1991) 34: 63-70
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