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BackgroundMutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion.MethodsVarious mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration.ResultsPiezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed postsurgical lymphedema development.ConclusionsPiezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.

To investigate demographic and physiological variables associated with clinically significant edema after upper eyelid surgery. A retrospective chart review was performed on patients who underwent blepharoplasty or external levator advancement with or without lid crease formation between January 2018 and January 2021 at the University of Southern California. Age, sex, pertinent medical history (medications causing edema and comorbidities), and pertinent surgical procedures were all collected. Postoperative photos were graded by two independent physician graders on a newly developed photographic scale ranging from 0 (no edema) to 3 (severe edema). Clinically significant edema of the eyelids was defined as Grade 3 edema at any postoperative point or ≥ Grade 1 edema after 90 days post operation. Patients without postoperative photos were excluded. Mann–Whitney U test , Fisher's exact test, and χ2 test were used to compare groups with and without significant edema. All analyses were conducted using SAS version 9.4 (SAS Institute Inc.) with α=0.05. Out of 217 patients, East Asian participants had higher odds of developing edema than White participants (odds ratio, 7.92; CI, 3.15–19.93, p < 0.0001) and Hispanic participants (odds ratio, 3.47; CI, 1.51–7.97, p = 0.003). Southeast Asian participants also had higher odds of developing CSEE than White participants (odds ratio, 6.19; CI, 1.71–22.43, p = 0.006). Fifty-four (24.9%) patients had clinically significant edema. Although BMI, medical comorbidities, medication use, and age did not affect edema, there was a statistically significant relationship between race and incidence of edema (p = 0.0001). Those in the CSEE group were also more likely to require reoperation (p = 0.0143). There is a statistically significant relationship between Asian race and the incidence of clinically significant eyelid edema. CSEE is associated with a higher incidence of reoperation [ABSTRACT FROM AUTHOR]

Background: Patients undergoing surgical treatment for solid tumors are at risk for development of secondary lymphedema due to intraoperative lymphatic vessel injury. The damaged lymphatic vessels fail to adequately regenerate and lymphatic obstruction leads to fluid and protein accumulation in the interstitial space and chronic lymphedema develops as a result. There are currently no effective pharmacological agents that reduce the risk of developing lymphedema or treat pre-existing lymphedema, and management is largely palliative. The present study investigated the efficacy of various 9-cis retinoic acid (9-cis RA) dosing strategies in reducing postsurgical lymphedema by utilizing a well-established mouse tail lymphedema model. Methods and Results: Short-duration treatment with 9-cis RA did not demonstrate a significant reduction in postoperative tail volume, nor an improvement in lymphatic clearance. However, long-term treatment with 9-cis RA resulted in decreased overall tail volume, dermal thickness, and epidermal thickness, with an associated increase in functional lymphatic clearance and lymphatic vessel density, assessed by LYVE-1 immunostaining, compared with control. These effects were seen at the site of lymphatic injury, with no significant changes observed in uninjured sites such as ear skin and the diaphragm. Conclusions: Given the reported results indicating that 9-cis RA is a potent promoter of lymphangiogenesis and improved lymphatic clearance at sites of lymphatic injury, investigation of postoperative 9-cis RA administration to patients at high risk of developing lymphedema may demonstrate positive efficacy and reduced rates of postsurgical lymphedema. [ABSTRACT FROM AUTHOR]

Background: Contact dermatitis (CD) affects ∼15% of the general population over a lifetime. However, there is a lack of epidemiological studies on treatment patterns for CD. Objective: We aim to analyze the patient characteristics and prescribing patterns among dermatologists and general practitioners (GPs) (internal medicine [IM] and family medicine [FM]) for CD in the United States. Methods: We conducted a population-based study using the National Ambulatory Medical Care Survey. Results: We identified 178,017,680 weighted patient visits for CD from 2001 to 2016. Dermatologists saw more white and non-Hispanic patients than GPs. GPs were less likely to prescribe ultrahigh potency topical corticosteroids (FM OR 0.27; P < 0.001, IM OR 0.41; P < 0.001) and more likely to prescribe oral antihistamines (FM OR 3.71; P < 0.001, IM OR 3.56; P < 0.001), oral corticosteroids (FM OR 5.35; P < 0.001, IM OR 6.87; P < 0.001), and injectable corticosteroids (FM OR 3.42; P = 0.006, IM OR 5.68; P < 0.001) than dermatologists. Conclusions: Across CD visits, GPs were less likely than dermatologists to prescribe ultrahigh potency topical corticosteroids and more likely than dermatologists to prescribe oral antihistamines and systemic corticosteroid therapy.