Accurate segregation of chromosomes in mitosis is ensured by a surveillance mechanism called the mitotic (or spindle assembly) checkpoint. It prevents sister chromatid separation until all chromosomes are correctly attached to the mitotic spindle through their kinetochores. The checkpoint acts by inhibiting the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets for degradation securin, an inhibitor of anaphase initiation. The activity of APC/C is inhibited by a mitotic checkpoint complex (MCC), composed of the APC/C activator Cdc20 bound to the checkpoint proteins MAD2, BubR1, and Bub3. When all kinetochores acquire bipolar attachment the checkpoint is inactivated, but the mechanisms of checkpoint inactivation are not understood. We have previously observed that hydrolyzable ATP is required for exit from checkpoint-arrested state. In this investigation we examined the possibility that ATP hydrolysis in exit from checkpoint is linked to the action of the Mad2-binding protein p31 comet in this process. It is known that p31 comet prevents the formation of a Mad2 dimer that it thought to be important for turning on the mitotic checkpoint. This explains how p31 comet blocks the activation of the checkpoint but not how it promotes its inactivation. Using extracts from checkpoint-arrested cells and MCC isolated from such extracts, we now show that p31 comet causes the disassembly of MCC and that this process requires β,γ-hydrolyzable ATP. Although p31 comet binds to Mad2, it promotes the dissociation of Cdc20 from BubR1 in MCC.
ObjectiveTo evaluate the Weill Cornell Medical College (WCMC)/New York Presbyterian Hospital (NYPH) experience with intraoperative frozen (IOF) section in the management of thyroid nodules with a fine needle aspiration (FNA) diagnosis of Bethesda II–VI and to analyze the cost and pathology benefit it provides.MethodsThe surgical and cytopathology files at WCMC/NYPH were searched within the time period of January 2008 to May 2013. A total of 435 thyroid specimens were identified for which both an FNA and subsequent IOF section was performed. The FNA was correlated with the locations of the resected nodule and the nodule frozen for intraoperative diagnosis. The results of the FNA were compared to the IOF section diagnosis and final diagnosis (FD).ResultsAmong 435 cases, the FNA diagnosis was Bethesda II: 149 cases, Bethesda III: 170 cases, Bethesda IV: 91 cases, Bethesda V: 19 cases, and Bethesda VI: 6 cases. There were a total of 83 carcinomas identified on FD, which included 69 papillary thyroid carcinomas (PTCs), 12 follicular carcinomas, and 2 poorly differentiated carcinomas. The preoperative FNA diagnosis for these carcinomas was as follows: Bethesda II, 11/149 (7.4%), Bethesda III, 24/170 (14%), Bethesda IV, 26/91 (29%), Bethesda V, 16/19 (84%), and Bethesda VI, 6/6 (100%). IOF section contributed to the diagnosis of malignancy in 16/429 (4%) cases: 1/149 (0.7%) Bethesda II, 5/170 (3%) Bethesda III, 2/91 (1.1%) Bethesda IV, and 8/19 (42%) Bethesda V. The diagnosis of malignancy was confirmed in the 6 Bethesda VI cases by IOF section. There were no false positives on IOF section. IOF had a sensitivity and specificity of 26% and 100%, respectively.ConclusionThe role of IOF section is limited in the evaluation of thyroid nodules. IOF section is most useful for nodules with an FNA diagnosis of Bethesda V lesions. The diagnosis of follicular variant of PTC remains difficult on frozen section.
BACKGROUND: Low birth weight (LBW) neonates have impaired kidney development that leaves them susceptible to kidney disease and hypertension during adulthood. The study here identifies events that blunt nephrogenesis and kidney development in the murine LBW neonate. METHODS: We examined survival, kidney development, GFR, gene expression, and cyto-/chemokines in the LBW offspring of malnourished (caloric and protein-restricted) pregnant mice. RESULTS: Malnourished pregnant mothers gave birth to LBW neonates that had 40% reduced body weight and 54% decreased survival. Renal blood perfusion was reduced by 37%, whereas kidney volume and GFR were diminished in the LBW neonate. During gestation, the LBW neonatal kidney had 2.2-fold increased apoptosis, 76% decreased SIX2+ progenitor cells, downregulation of mesenchymal-to-epithelial signaling factors Wnt9b and Fgf8, 64% less renal vesicle formation, and 32% fewer nephrons than controls. At birth, increased plasma levels of IL-1β, IL-6, IL-12(p70), and granulocyte-macrophage colony-stimulating factor in the LBW neonate reduced SIX2+ progenitor cells. CONCLUSION: Increased pro-inflammatory cytokines in the LBW neonate decrease SIX2+ stem cells in the developing kidney. Reduced renal stem cells (along with the decreased mesenchymal-to-epithelial signaling) blunt renal vesicle generation, nephron formation, and kidney development. Subsequently, the mouse LBW neonate has reduced glomeruli volume, renal perfusion, and GFR.
Background/Aims: Preoperative identification of malignant parotid lesions remains challenging, and thus, some surgeons use frozen section (FS) to assist them in their decision making. We evaluated the pathologic and cost benefit of FS after fine-needle aspiration (FNA) at our institution. Methods: We assessed medical data for 260 patients undergoing parotidectomy with FS. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were calculated for radiology, FNA, and FS. Results: The sensitivities, specificities, and accuracies of FNA and FS were 75.0, 96.4, and 93.2%, and 75.0, 100, and 96.8%, respectively. FS detected 0% of FNA false negatives and 80% of false positives. The additional pathology charge for FS alone per correctly identified benign lesion after a positive FNA was USD 1,443. Conclusion: FNA and FS are more reliable in the prognostication of the final pathology than radiology. At our center, FS appears to be of limited clinical use after benign FNAs, but may be more useful after positive, indeterminate, and nondiagnostic FNAs.
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