In cancer, VEGF-induced increase in vascular permeability results in increased interstitial pressure, reducing perfusion and increasing hypoxia, which reduce delivery of chemotherapeutic agents and increase resistance to ionizing radiation. Here, we show that both TIMP-2 and Ala ؉ TIMP-2, a TIMP-2 mutant without matrix metalloproteinase inhibitory activity, antagonize the VEGF-A-induced increase in vascular permeability, both in vitro and in vivo. Like other agents known to preserve endothelial barrier function, TIMP-2 elevates cytosolic levels of cAMP and increases cytoskeletal-associated vascular endothelial cadherin in human microvascular endothelial cells. All of these effects are completely ablated by selective knockdown of integrin ␣3␤1 expression, expression of a dominant negative protein tyrosine phosphatase Shp-1 mutant, administration of the protein tyrosine phosphatase inhibitor orthovanadate, or the adenylate cyclase inhibitor SQ22536. This TIMP-2-mediated inhibition of vascular permeability involves an integrin ␣3␤1-Shp-1-cAMP/protein kinase A-dependent vascular endothelial cadherin cytoskeletal association, as evidenced by using siRNAs to integrin ␣3␤1 and Shp-1, or treatment with Shp-1 inhibitor NSC87877 and protein kinase A inhibitor H89. Our results demonstrate the potential utility for TIMP-2 in cancer therapy through "normalization" of vascular permeability in addition to previously described antiangiogenic effects. (Blood. 2012;120(24):4892-4902) IntroductionTumor-associated angiogenesis is critical for tumor progression and metastasis. The central role of vascular endothelial growth factor-A (VEGF-A) in this process is evidenced by the development and approval of bevacizumab, a VEGF-A neutralizing antibody, for therapy in several human cancers. VEGF-A-induced angiogenesis is often accompanied by increased vascular permeability, which can result in fibrin deposition and may facilitate tumor cell extravasation enhancing metastasis formation. 1 The resulting vascular leak has also been shown to increase interstitial pressure within the tumor, decrease tumor blood flow, and hinder drug delivery to the tumor. Indeed, it has been proposed that VEGF-axis targeted therapies may result in "normalization" of tumor vasculature improving chemotherapeutic delivery and decreasing hypoxia, resulting in enhanced radiosensitivity. 2,3 Vascular permeability can be modulated by the phosphorylation, cleavage, and internalization of vascular endothelial (VE)-cadherin. [4][5][6] Tyrosine phosphorylation of the cadherin-catenin complexes is regulated by the activities of protein tyrosine phosphatases and src-family kinases. 7-11 Inhibition of tyrosine phosphorylation of VE-cadherin increases the stability of adherens junctions and improves vascular barrier function. Matrix metalloproteinase (MMP)-mediated cleavage of VE-cadherin may promote vascular permeability and cell proliferation by dissociating cadherin-catenin complex and disrupting cell-cell adhesion. [12][13][14][15] In contrast, it is widely recognized t...

The Supportive Care Needs Framework has potential utility in the development of patient-centred support services or healthcare policies and serves as an important base for further studies; especially, specific examples of each supportive care needs domain can guide in clinical settings when healthcare professionals provide multidisciplinary care to amyotrophic lateral sclerosis/motor neuron disease patients and individualised care.

The objective of this study was to compare the cost of illness of amyotrophic lateral sclerosis (ALS) in the Korean population based on the staging system for ALS from the perspective of both patients and the government. Direct medical costs, care-related costs, and loss of productivity in patients with ALS were measured based on medical records and face-to-face interviews. The patients were divided into groups according to the staging system for ALS, and the cost of illness was analysed. A total of 151 patients with ALS were enrolled in the study. The mean monthly cost of ALS was US $7902 per patient and increased according to the disease stage (stage 2, US $5181; stage 3, US $7089; stage 4, US $10,557). Of direct medical costs (US $3436), 44.8% of the cost burden was carried by patients, and the remaining costs were paid by the government. In conclusion, although the current coverage rate of the National Health Insurance (NHI) system for rare and intractable diseases including ALS is 90%, the rate of direct medical costs paid by patients and out-of-pocket costs remain high. Moreover, coverage rates and cost of illness are closely related with disease severity.

The rhodium‐catalyzed selective cyanation of CH bonds of indolines and indoles with N‐cyano‐N‐phenyl‐para‐methylbenzenesulfonamide is described. This protocol offers a facile access to C‐7 cyanated indolines and C‐2 cyanated indoles with high site selectivity and excellent functional group tolerance.magnified image

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Purpose: This bibliometric study investigated the current state of documents on coronavirus disease 2019 (COVID-19) published in nursing journals. The analysis focused on the description of most productive journals, institutions, and countries, as well as the characteristics of the documents.Methods: The publications analyzed in this study were retrieved from the Web of Science database with search keywords. The searches used to establish the study dataset were last updated on July 10, 2020. The inclusion criteria were relevant English-language publications in journals published in the Science Citation Index Expanded or Social Science Citation Index. Content analysis of original articles and reviews was done.Results: An analysis of 125 publications on COVID-19 from 48 journals showed that the most productive journal and country were the Journal of Clinical Nursing (n = 18) and the USA (n = 53), respectively. Original articles (n = 27, 21.6%) and review papers (n = 4, 3.2%) accounted for 24.8% of the articles, and the highest number of papers were found in early access (published ahead of print) (n = 51, 40.8%) and Q1 journals (n = 73, 58.4%). The content analysis found 10 data-based original articles or reviews, which dealt with the topics of nurse training (n = 2), nurses’ psychosocial status (n = 2), nursing research methodology (n = 1), nursing guidelines (n = 4), and protection for nurses (n = 1).Conclusion: This study presents the current situation of nursing research on COVID-19 based on an analysis of publications in nursing journals and provides meaningful information to nursing researchers and editorial board members. The number of data-based original articles on nursing related to COVID-19 remains low.

This paper mainly focuses on the accurate estimation of the vehicle velocities of all axes, using the data received from a low-cost 6-D inertial measurement unit. The data include the vehicle linear acceleration and angular rates of all axes. In addition, the observer uses the wheel speed sensors and steering wheel angle information, which are already available on most recent production cars. Utilizing the aforementioned information, based on the combination of a bicycle model and a kinematic model, a multiple-observer system that computes the weighted sum estimation that is dependent on cornering stiffness adaptation is adopted to observe the lateral vehicle velocity, as well as longitudinal and vertical velocities. The stability of each component of the proposed observer is investigated, and a set of assessments to confirm the performance of the entire system is arranged through experiments using a real production sport utility vehicle.