YES kinase controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis

Vascular Endothelial (VE)-cadherin in endothelial adherens junctions is an essential component of the vascular barrier, critical for tissue homeostasis and implicated in progression of diseases such as cancer and eye diseases. Inhibitors of SRC cytoplasmic tyrosine kinase have been applied to suppress tyrosine phosphorylation of VE-cadherin and thereby to prevent excessive leakage, edema and high interstitial pressure. We show that the SRC-related YES tyrosine kinase rather than SRC, is localized at endothelial cell (EC) junctions. EC-specific YES deletion suppresses VE-cadherin phosphorylation, and arrests VE-cadherin at EC junctions. This is accompanied by loss of EC collective migration, and exaggerated agonist-induced macromolecular leakage, while extravasation of monocytes is suppressed. Overexpression of Yes causes ectopic VE-cadherin phosphorylation while vascular leakage is unaffected. In contrast, in EC-specific Src-deficient mice, VE-cadherin internalization is maintained and leakage is suppressed. In conclusion, YES-mediated VE-cadherin phosphorylation regulates its constitutive turnover, required for endothelial junction plasticity and vascular integrity.

Computational modeling of PET tracer distribution in solid tumors integrating microvasculature

Background We present computational modeling of positron emission tomography radiotracer uptake with consideration of blood flow and interstitial fluid flow, performing spatiotemporally-coupled modeling of uptake and integrating the microvasculature. In our mathematical modeling, the uptake of fluorodeoxyglucose F-18 (FDG) was simulated based on the Convection–Diffusion–Reaction equation given its high accuracy and reliability in modeling of transport phenomena. In the proposed model, blood flow and interstitial flow are solved simultaneously to calculate interstitial pressure and velocity distribution inside cancer and normal tissues. As a result, the spatiotemporal distribution of the FDG tracer is calculated based on velocity and pressure distributions in both kinds of tissues. Results Interstitial pressure has maximum value in the tumor region compared to surrounding tissue. In addition, interstitial fluid velocity is extremely low in the entire computational domain indicating that convection can be neglected without effecting results noticeably. Furthermore, our results illustrate that the total concentration of FDG in the tumor region is an order of magnitude larger than in surrounding normal tissue, due to lack of functional lymphatic drainage system and also highly-permeable microvessels in tumors. The magnitude of the free tracer and metabolized (phosphorylated) radiotracer concentrations followed very different trends over the entire time period, regardless of tissue type (tumor vs. normal). Conclusion Our spatiotemporally-coupled modeling provides helpful tools towards improved understanding and quantification of in vivo preclinical and clinical studies.

A Rare Case Report of Life-Threatening Severe Protein-Losing Gastroenteropathy

Protein-losing gastroenteropathy is a rare syndrome of protein loss from the gastrointestinal system. It manifests with hypoproteinemic edema, which may be due to either lymphatic leakage due to increased interstitial pressure or leakage of protein-rich fluids due to intestinal disorders. Our case describes a 65-year-old female with life-threatening protein-losing enteropathy (PLE) requiring multiple transfers to intensive care unit for vasopressor support. In this rare instance, her extensive initial workup did not reveal any etiology for PLE, but she was later found to have underlying Crohn’s colitis. Protein-losing enteropathy is an underdiagnosed complication of inflammatory bowel disease and must be considered while treating patients with colitis.

A Rare Case of Nsaid Induced Gastric Body Diaphragmatic-Like Stricture

Protein-losing gastroenteropathy is a rare syndrome of protein loss from the gastrointestinal system. It manifests with hypoproteinemic edema, which may be due to either lymphatic leakage due to increased interstitial pressure or leakage of protein-rich fluids due to intestinal disorders. Our case describes a 65-year-old female with life-threatening protein-losing enteropathy (PLE) requiring multiple transfers to intensive care unit for vasopressor support. In this rare instance, her extensive initial workup did not reveal any etiology for PLE, but she was later found to have underlying Crohn’s colitis. Protein-losing enteropathy is an underdiagnosed complication of inflammatory bowel disease and must be considered while treating patients with colitis.

Pyroelectric Catalysis-based “Nano-lymphatic” Reduces Tumor Interstitial Pressure for Enhanced Penetration and Hydrodynamic Therapy

Owing to deficiency of lymphatic reflux in the tumor, the retention of tumor interstitial fluid causes the aggravation of tumor interstitial pressure (TIP), which leads to unsatisfactory tumor penetration of nanomedicine. It is the main inducement of tumor recurrence and metastasis. Herein, we design a pyroelectric catalysis-based “Nano-lymphatic” to decrease the TIP for enhanced tumor penetration and treatments. It realizes photothermal therapy and decomposition of tumor interstitial fluid under NIR-II laser irradiation after reaching the tumor, which reduces the TIP for enhanced tumor penetration. Simultaneously, reactive oxygen species generated during the pyroelectric catalysis can further damage deep tumor stem cells. The results indicate that the “Nano-lymphatic” relieves 52% of TIP, leading to enhanced tumor penetration, which effectively inhibits the tumor proliferation (93.75%) and recurrence. Our finding presents a novel strategy to reduce TIP by pyroelectric catalysis for enhanced tumor penetration and improved treatments, which is of great significance for drug delivery.

DETERMINATION OF CLINICAL INDICATORS OF INTERSTITIAL PRESSURE IN DEEP AND BORDERLINE BURNS DEPENDING ON THE TIME OF THERMAL INJURY

Summary. Objective. Improvement of the diagnosis of compartment syndrome depending on the time of thermal injury and the establishment of indications for draining operations. Materials and methods. Interstitial pressure was studied in 66 victims who were admitted to the burn center in the first 24 hours after the injury. The patients were divided into groups depending on the relative extent of the lesion and the length of hospitalization. The results of the study and their discussion. Upon admission of the patient to the department, a thorough sanitation of the burn surfaces was performed with antiseptic solutions (chlorhexidine, dekasan). In the burn area, the interstitial pressure was measured in all muscle groups deeper than the superficial fascia with a Kompartment druck Monitor System (MIPM Mammen dorfer Institut für Physik und Medizin Gmbh) apparatus for measuring interstitial pressure. Depending on the level of interstitial pressure, patients underwent conservative drug and infusion therapy aimed at reducing edema and hypoxia of damaged tissues. In the case of critical indicators of interstitial pressure, an urgent surgical intervention was performed for the purpose of decompression. When assessing the dependence of the pressure level in the tissues on the timing of burns, there is a clear dependence in all observation groups: late hospitalizations are accompanied by a large increase in pressure, the level of circular location of burns on the extremities is of great importance for high blood pressure. Conclusion. It has been determined that objectification of the diagnosis of the compartment syndrome in order to prevent ischemic tissue damage plays an important role in deep and borderline burns. Clinical indicators of tissue pressure in deep and borderline burns have been established, depending on the time of thermal injury, which allows the diagnosis of compartment syndrome and the establishment of indications for drug, infusion therapy and urgent drainage operations.