Repression of MAPK/Erk signaling by Efnb2-Ephb4-Rasa1 is required for lymphatic valve formation

The lymphatic vascular system plays important roles in various physiological and pathological processes, and lack of lymphatic or lymphovenous valves always causes lymph or blood reflux, and can lead to lymphedema. However, the molecular mechanism underlying the valve formation is poorly understood. Here we report that the MAPK/Erk signaling needs to be repressed during the valve-forming lymphatic endothelial cells (LECs) fate determination, which differs from its positive role in the LECs specification. Up-regulation of MAPK/Erk signaling in ephb4b, efnb2a;efnb2b and rasa1a;rasa1b mutants leads to lymphatic valve defects, whereas simultaneous loss of Erk1 and Erk2 causes valve hyperplasia. Moreover, valve defects in ephb4b or rasa1a;rasa1b mutants are mitigated in the presence of MEK inhibitors, indicating a new function of Efnb2-Ephb4-Rasa1 cassette in lymphatic valve progenitor cells specification by repressing MAPK/Erk activity. Therefore, our findings provide a mechanistic understanding of the lymphatic valve formation and potential drug targets for related lymphatic diseases.

Immature Plasma Cell Myeloma Mimics Metastatic Renal Cell Carcinoma on 18F-PSMA-1007 PET/CT Due to Endothelial PSMA-Expression

We present a 71-year-old female patient who underwent 18F-PSMA-1007 PET/CT for suspected metastatic renal cell carcinoma (RCC), as RCC also shows high PSMA-expression in tumor neovascularization. 18F-PSMA-1007 PET/CT showed a high PSMA-avidity in the renal tumor, enlarged intra-abdominal and mediastinal lymph nodes. Moreover, PSMA-positive pleural, pulmonal and osseous lesions were found. However, histopathology revealed an immature plasma cell myeloma with an endothelial PSMA-expression of the neovasculature. This case illustrates the increased PSMA-avidity in multiple myeloma and highlights PSMA as a potential theragnostic target in multiple myeloma. For clinical routine, lymphatic diseases such as extramedullary myeloma should be considered as differential diagnosis in PSMA-avid renal masses on PET/CT.

Lymphangion-Chip: a microphysiological system which supports co-culture and bidirectional signaling of lymphatic endothelial and muscle cells

The pathophysiology of several lymphatic diseases, such as lymphedema, depends on the function of lymphangions that drive lymph flow. Even though the signaling between two main cellular components of a...

Medicine and Phlebolymphology: Time to Change?

Biomedical science is undergoing a reappraisal of its scientific advancement process and of the related healthcare management. Progress in medicine should combine improvements of knowledge, efficacy, and safety of diagnostic/therapeutic procedures, with adequate cost-effectiveness profiles. This narrative review is aimed at assessing in medicine, more specifically in phlebology and lymphology: (a) scientific literature possible biases, (b) the level of evidence, comprehensiveness, and cost-effectiveness of the main therapeutic options, and (c) the possible contribution of integrative and translational medicine. Current medical research may have cognitive biases, or industry-tied influences, which impacts clinical practice. Some reductionism, with an increasing use of drugs and technology, often neglecting the understanding and care of the root causative pathways of the diseases, is affecting biomedical science as well. Aging brings a relevant burden of chronic degenerative diseases and disabilities, with relevant socio-economic repercussions; thus, a major attention to cost-effectiveness and appropriateness of healthcare is warranted. In this scenario, costly and innovative but relatively validated therapies may tend to be adopted in venous and lymphatic diseases, such as varicose veins, leg venous ulcer, post-thrombotic syndrome, pelvic congestion syndrome, and lymphedema. Conversely, a more comprehensive approach to the basic pathophysiology of chronic venous and lymphatic insufficiency and the inclusion of pharmacoeconomics analyses would benefit overall patients’ management. Erroneous lifestyle and nutrition, together with chronic stress-induced syndromes, significantly influence chronic degenerative phlebo-lymphatic diseases. The main active epigenetic socio-biologic factors are obesity, dysfunctions of musculo-respiratory-vascular pumps, pro-inflammatory nutrition, hyperactivation of stress axis, and sedentarism. An overall critical view of the scientific evidence and innovations in phebolymphology could be of help to improve efficacy, safety, and sustainability of current practice. Translational and integrative medicine may contribute to a patient-centered approach. Conversely, reductionism, eminence/reimbursement-based decisional processes, patients’ lack of education, industry-influenced science, and physician’s improvable awareness, may compromise efficacy, safety, appropriateness, and cost-effectiveness of future diagnostic and therapeutic patterns of phlebology and lymphology.

Development and Feasibility of a Very Low-cost, Home-made, Near Infrared lymphatic Imaging Device

Introduction: Near Infrared (NIR), lymphatic Imaging is an emergent imaging technique used to assess superficial lymphatic structures and its function. It uses a NIR light source and a special camera that detects the fluorescence of a non-radioactive dye called indocyanine green (ICG), which is injected subdermally and its way through lymphatic capillaries, making this device useful in the diagnosis and follow up of lymphatic diseases. Objective: To show (NIR) step-by-step development of a feasible, user-friendly, and low-cost homemade Near Infrared (NIR) lymphatic imaging device. Methods: Using worldwide available components such as a customized laser and a modified webcam, we assembled what is a functional plug and play NIR lymphatic imaging device and evaluated its function with a 25-year-old healthy woman. Conclusion: It is feasible to build a functional, homemade, low-cost Near Infrared (NIR) lymphatic imaging device in a tenth of its value.

Abstract 17346: Loss of Neuropilin 2 Impairs Lymphangiogenesis and Exacerbates Lymphedema

Dysfunctional lymphatic networks can lead to lymphatic diseases such as lymphedema as well as aggravate cardiovascular diseases such as atherosclerosis and hypertension. Some primary lymphedema patients have mutations in the Neuropilin 2 ( NRP2 ) gene, which encodes a transmembrane receptor that acts with VEGFR3 for the ligands VEGF-C and VEGF-D. Nrp2 has been shown to be a key regulator of lymphatic vessel development in the neonate as global Nrp2 -deficient mice suffer from reduced lymphatic density. However, Nrp2 protein expression is dramatically downregulated after birth and its role in adult lymphangiogenesis or its relevance in lymphedema is less clear. Our hypothesis is that Nrp2 expression is necessary for optimal lymphangiogenesis and proper lymphatic drainage function in the adult, and that loss of Nrp2 , either genetically or transcriptionally via down-regulation by specific transcription factors, may worsen lymphedema. In acute and chronic mouse inflammation models, we found that loss of Nrp2 specifically in the lymphatic endothelium ( prox1-cre ERT2 ;Nrp2 f/f ) resulted in prolonged swelling and reduced lymphatic drainage compared to control mice. Using the VEGFC-induced corneal lymphangiogenesis model and the tail wound-induced secondary lymphedema model, LEC-Nrp2-iKO mice showed diminished lymphangiogenesis and reduced lymphatic drainage compared to littermate controls. Furthermore, primary mouse dermal LEC isolated from Nrp2-iKO mice reveal suppressed VEGFR3 activation, signaling, and proliferation following VEGF-C stimulation, compared to LEC isolated from control mice. Collectively, our results identify Nrp2 as a critical mediator of lymphangiogenesis and homeostatic lymphatic drainage function in adult tissues.

Lymphedema resulting from filariasis successfully treated by surgery

Filariasis is an infectious disease caused by a filarial worm infection transmitted by mosquito bites. The disease can result in reduced work productivity, disability and social stigma. This disease transmission process begins when a mosquito bite and suck the blood containing the microfilaria. Filarial infections have been grouped into three categories based on their location diseases of the disease: (1) lymphatics, (2) skin, and (3) body cavities. Morbidity is almost entirely due to the species that cause lymphatic diseases, and skin diseases to a lesser degree. A 28-year-old male came with a chief complaint of swollen right leg since four years ago which worsened in the last three months. Upon physical examination, edema, fibrosis, and hyper-pigmented plaques were present on the right lower extremity. The blood microfilariae examination was positive for Wuchereria bancrofti. The lymphedema did not resolve despite of antifilarial treatment and surgery was eventually performed to resect the fibrous tissue and subcutaneous edema. The patient responded well to the treatment with a significant reduction in the edema. No complication was present until two years after surgery.

The Epitome of Novel Techniques and Targeting Approaches in Drug Delivery for Treating Lymphatic Filariasis

Background: Lymphatic filariasis is a pervasive and life-threatening disease for human beings. Currently, 893 million people in 49 countries worldwide affected by lymphatic filariasis as per WHO statistics. The concealed aspects of lymphatic diseases such as delayed disease detection, inappropriate disease imaging, the geographical outbreak of infection, and lack of preventive chemotherapy have brought this epidemic to the edge of Neglected Tropical Diseases. Many medications and natural bioactive substances have seen to promote filaricidal activity against the target parasitic species. However, the majority of failures have occurred in pharmaceutical and pharmacokinetic issues. Objective: The purpose of the study is to focus on the challenges and therapeutic issues in the treatment of filariasis. The review brings novel techniques and therapeutic approaches for combating lymphatic filariasis. It also offers significant developments and opportunities for such therapeutic interventions. Conclusion: Through this review, an attempt has made to critically evaluate the avenues of innovative pharmaceuticals and molecular targeting approaches to bring an integrated solution to combat lymphatic filariasis.