Breast cancer-related lymphedema results in impaired epidermal differentiation and tight junction dysfunction.

Breast cancer-related lymphedema (BCRL) is characterized by skin changes, swelling, fibrosis, and recurrent skin infections. Clinical studies have suggested that lymphedema results in skin barrier defects; however, the underlying cellular mechanisms and the effects of bacterial contamination on skin barrier function remain unknown. In matched biopsies from patients with unilateral BCRL, we observed decreased expression of filaggrin and the tight junction protein zona occludens-1 (ZO-1) in skin affected by moderate lymphedema, or by subclinical lymphedema in which dermal backflow of lymph was identified by indocyanine green lymphography, relative to controls (areas without backflow and from the unaffected arm). In vitro stimulation of keratinocytes with lymph fluid obtained from patients undergoing lymphedema surgery led to the same changes, as well as increased expression of keratin 14, a marker of immature keratinocytes. Finally, using mouse models of lymphedema, we showed that like the clinical scenario, the expression of skin barrier proteins was decreased relative to normal skin and that colonization with S. epidermidis bacteria amplified this effect, as well as lymphedema severity. Taken together, our findings suggest that lymphatic fluid stasis contributes to skin barrier dysfunction in lymphedema.

Lack of Racial Diversity in Surgery and Pathology Textbooks Depicting Diseases of the Breast.

INTRODUCTION: The lack of racial diversity depicted in medical education texts may contribute to an implicit racial bias among clinicians. This bias influences outcomes, as familiarity with the various cutaneous manifestations of disease is essential to making an accurate diagnosis. To better understand the racial disparities in breast surgery, we sought to determine the extent of skin tone representation depicted in images of breast surgery and pathology textbooks. METHODS: Textbooks were screened for color images of conditions with sufficient skin tissue present to assign the Fitzpatrick skin phototype (FSP). Figures were independently assigned an FP score (range: 1-6), and subdivided into "light skin" (FP 1-3) and "dark skin" (FP 4-6). Number of figures in each category and percentage of patients with each skin tone were calculated. RESULTS: 557 figures were included. Among 12 textbooks reviewed, seven textbooks were from the discipline of surgery, while five were pathology-related. Textbook year of publication spanned from 1996 to 2018. Overall, 533 (95.7%) figures depicted patients with light skin color versus 24 (4.3%) with dark skin color. There was no association between FP score and year of textbook publication (P = 0.69). CONCLUSIONS: Patient images in breast textbooks are overwhelmingly of light skin tones, excluding patients with darker skin tones. The dearth of images depicting dark skinned individuals did not improve over time. Inclusion of patients of color in future textbooks may help reduce racial disparities within breast cancer care.

Dysregulation of Lymphatic Endothelial VEGFR3 Signaling in Disease.

Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), a receptor tyrosine kinase encoded by the FLT4 gene, plays a significant role in the morphogenesis and maintenance of lymphatic vessels. Under both normal and pathologic conditions, VEGF-C and VEGF-D bind VEGFR3 on the surface of lymphatic endothelial cells (LECs) and induce lymphatic proliferation, migration, and survival by activating intracellular PI3K-Akt and MAPK-ERK signaling pathways. Impaired lymphatic function and VEGFR3 signaling has been linked with a myriad of commonly encountered clinical conditions. This review provides a brief overview of intracellular VEGFR3 signaling in LECs and explores examples of dysregulated VEGFR3 signaling in various disease states, including (1) lymphedema, (2) tumor growth and metastasis, (3) obesity and metabolic syndrome, (4) organ transplant rejection, and (5) autoimmune disorders. A more complete understanding of the molecular mechanisms underlying the lymphatic pathology of each disease will allow for the development of novel strategies to treat these chronic and often debilitating illnesses.

Physical activity RX: development and implementation of physical activity counselling and prescription learning objectives for Canadian medical school curriculum.

Physical activity is an important component of health and well-being, and is effective in the prevention, management, and treatment of numerous non-communicable chronic diseases. Despite the known health benefits of physical activity in all populations, most Canadians do not meet physical activity recommendations. Physicians play a key role in assessing, counselling, and prescribing physical activity. Unfortunately, many barriers, including the lack of adequate education and training, prevent physicians from promoting this essential health behaviour. To support Canadian medical schools in physical activity curriculum development, a team of researchers, physicians, and exercise physiologists collaborated to develop a key set of learning objectives deemed essential to physician education in physical activity counselling and prescription. This commentary will review the newly developed Canadian Physical Activity Counselling Learning Objectives and give case examples of three Canadian medical schools that have implemented these learning objectives.

L'activité physique est une composante importante de la santé et du bien-être, et elle est efficace dans la prévention, la prise en charge et le traitement de nombreuses maladies chroniques non transmissibles. Malgré les bienfaits qu'on lui reconnaît pour la santé des populations, la plupart des Canadiens ne suivent pas les recommandations en matière d'exercice. Les médecins jouent un rôle clé dans l'évaluation, le counseling et la prescription de l'activité physique, mais de nombreux obstacles, dont le manque de formation adéquate, les empêchent de promouvoir cette habitude de vie essentielle pour la santé. Afin d'aider les facultés de médecine canadiennes dans l'élaboration de leur cursus sur l'activité physique, une équipe composée de chercheurs, de médecins et de physiologistes de l'exercice a collaboré à la définition d'un ensemble d'objectifs d'apprentissage jugés indispensables à la formation des médecins pour qu'ils puissent offrir des conseils sur l'activité physique et la prescrire. Ce commentaire passe en revue les nouveaux objectifs d'apprentissage en matière de counseling en activité physique et donne des exemples de cas de trois facultés de médecine canadiennes qui ont mis en œuvre ces objectifs d'apprentissage.

Isoform-specific functions of PPARγ in gene regulation and metabolism.

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPARγ by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPARγ isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. Strikingly, although PPARγ1 and PPARγ2 contain identical DNA binding domains, we uncovered isoform-specific genomic binding sites in addition to shared sites. Moreover, PPARγ1 and PPARγ2 regulated a different set of genes in adipose tissue depots, suggesting distinct roles in adipocyte biology. Indeed, mice with selective deficiency of PPARγ1 maintained body temperature better than wild-type or PPARγ2-deficient mice. Most remarkably, although TZD treatment improved glucose tolerance in mice lacking either PPARγ1 or PPARγ2, the PPARγ1-deficient mice were protected from TZD-induced body weight gain compared with PPARγ2-deficient mice. Thus, PPARγ isoforms have specific and separable metabolic functions that may be targeted to improve therapy for insulin resistance and diabetes.