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Early sorting endosomes are responsible for the trafficking and function of transferrin receptor (TfR) and EGFR. These receptors play important roles in iron uptake and signaling and are critical for breast cancer development. However, the role of morphology, receptor composition, and signaling of early endosomes in breast cancer remains poorly understood. A novel population of enlarged early endosomes was identified in breast cancer cells and tumor xenografts but not in noncancerous MCF10A cells. Quantitative analysis of endosomal morphology, cargo sorting, EGFR activation, and Rab GTPase regulation was performed using superresolution and confocal microscopy followed by 3D rendering. MDA-MB-231 breast cancer cells have fewer, but larger EEA1positive early endosomes compared with MCF10A cells. Live-cell imaging indicated dysregulated cargo sorting, because EGF and Tf traffic together via enlarged endosomes in MDA-MB-231, but not in MCF10A. Large EEA1-positive MDA-MB-231 endosomes exhibited prolonged and increased EGF-induced activation of EGFR upon phosphorylation at tyrosine-1068 (EGFR-p1068). Rab4A overexpression in MCF10A cells produced EEA1-positive enlarged endosomes that displayed prolonged and amplified EGF-induced EGFR-p1068 activation. Knockdown of Rab4A lead to increased endosomal size in MCF10A, but not in MDA-MB-231 cells. Nevertheless, Rab4A knockdown resulted in enhanced EGF-induced activation of EGFR-p1068 in MDA-MB-231 as well as downstream signaling in MCF10A cells. Altogether, this extensive characterization of early endosomes in breast cancer cells has identified a Rab4-modulated enlarged early endosomal compartment as the site of prolonged and increased EGFR activation.Implications: Enlarged early endosomes play a Rab4-modulated role in regulation of EGFR activation in breast cancer cells.

Background:The cardiovascular health of transgender and gender diverse (TGD) persons, a growing population in the United States, has become a subject of heightened interest. We sought to assess the prevalence and predictors of cardiovascular disease (CVD) in transgender men, transgender women, and gender nonconforming persons in the United States. Methods: A cohort of individuals self-identified as TGD (ie, transgender or gender nonconforming) in the United States was identified using the 2018 Centers for Disease Control's Behavioral Risk Factor Surveillance Survey. Results: Among the 1019 TGD individuals studied, 378 (37.1%) identified their transition status as male-to-female, 394 (38.7%) as female-to-male, and the remaining 247 (24.2%) as gender nonconforming. A total of 138 (13.5%) had reported CVD, while 881 (86.5%) did not. The prevalence of CVD in TGD individuals identified as male-to-female, female-to-male, and gender nonconforming were noted to be similar (14.6% vs. 13.5% vs. 12.1%; P = 0.69). TGD persons with CVD were older with lower annual income. They also had higher rates of smoking, lower rates of regular exercise, and higher rates of smoking and chronic medical comorbidities. Independent predictors of CVD in TGD persons included older age, diabetes, chronic kidney disease, chronic obstructive pulmonary disease, and depressive disorder. Conclusions: In this contemporary cross-sectional nationally representative survey, CVD was prevalent in nearly 14% of TGD persons. Further studies examining interventions to reduce CV risk and enhance access to medical care in the TGD population are warranted.

Objectives:The objective of the study is to assess the skeletal, dental, and soft-tissue effects of PowerScope fixed functional appliance in Class II malocclusion. Materials and Methods: Fifteen late adolescent Class II subjects (CVMI Stages 5 and 6) were treated with fixed mechanotherapy and PowerScope fixed functional appliance. Student t-test was used to compare the cephalometric changes produced before insertion of appliance (T1) and 6 months after the treatment with this appliance (T2). Results: Maxillomandibular relationship improved with significant lengthening of the mandible. There was retroclination of maxillary incisors, proclination of mandibular incisors, extrusion, and sagittal displacement of mandibular molars and clockwise rotation of occlusal plane. Conclusion: PowerScope is effective in correcting Class II malocclusion with a combination of dentoalveolar (primarily) and skeletal changes. abstRactThis is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

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