促血管生成素-1与血管通透性调节

Angiopoietin-1 (Ang-1) is a newly-found endothelium-specific proangiogenic factor and it had been proved essential roles in both vasculogenesis and angiogensis. Among them, its anti - leakage abihty may have great potential apphcations in chnical treatment of vascular hyper-permeability in a variety of diseases such as cancer, diabetic retinopathy, rheumatoid arthritis, asthma. In this review, some research progresses focused on this aspect are discussed.     

cAMP‐induced activation of protein kinase A and p190B RhoGAP mediates down‐regulation of TC10 activity at the plasma membrane and neurite outgrowth

Cyclic AMP plays a pivotal role in neurite growth. During outgrowth, a trafficking system supplies membrane at growth cones. However, the cAMP‐induced signaling leading to the regulation of membrane trafficking remains unknown. TC10 is a Rho family GTPase that is essential for specific types of vesicular trafficking. Recent studies have shown a role of TC10 in neurite growth in NGF‐treated PC12 cells. Here, we investigated a mechanical linkage between cAMP and TC10 in neuritogenesis. Plasmalemmal TC10 activity decreased abruptly after cAMP addition in neuronal cells. TC10 was locally inactivated at extending neurite tips in cAMP‐treated PC12 cells. TC10 depletion led to a decrease in cAMP‐induced neurite outgrowth. Constitutively active TC10 could not rescue this growth reduction, supporting our model for a role of GTP hydrolysis of TC10 in neuritogenesis by accelerating vesicle fusion. The cAMP‐induced TC10 inactivation was mediated by PKA. Considering cAMP‐induced RhoA inactivation, we found that p190B, but not p190A, mediated inactivation of TC10 and RhoA. Upon cAMP treatment, p190B was recruited to the plasma membrane. STEF depletion and Rac1‐N17 expression reduced cAMP‐induced TC10 inactivation. Together, the PKA‐STEF‐Rac1‐p190B pathway leading to inactivation of TC10 and RhoA at the plasma membrane plays an important role in cAMP‐induced neurite outgrowth.     

Regulation of microvascular permeability by vascular endothelial growth factors

Generation of new blood vessels from pre-existing vasculature (angiogenesis) is accompanied in almost all states by increased vascular permeability. This is true in physiological as well as pathological angiogenesis, but is more marked during disease states. Physiological angiogenesis occurs during tissue growth and repair in adult tissues, as well as during development. Pathological angiogenesis is seen in a wide variety of diseases, which include all the major causes of mortality in the west: heart disease, cancer, stroke, vascular disease and diabetes. Angiogenesis is regulated by vascular growth factors, particularly the vascular endothelial growth factor family of proteins (VEGF). These act on two specific receptors in the vascular system (VEGF-R1 and 2) to stimulate new vessel growth. VEGFs also directly stimulate increased vascular permeability to water and large-molecular-weight proteins. We have shown that VEGFs increase vascular permeability in mesenteric microvessels by stimulation of tyrosine auto-phosphorylation of VEGF-R2 on endothelial cells, and subsequent activation of phospholipase C (PLC). This in turn causes increased production of diacylglycerol (DAG) that results in influx of calcium across the plasma membrane through store-independent cation channels. We have proposed that this influx is through DAG-mediated TRP channels. It is not known how this results in increased vascular permeability in endothelial cells in vivo. It has been shown, however, that VEGF can stimulate formation of a variety of pathways through the endothelial cell, including transcellular gaps, vesiculovacuolar organelle formation, and fenestrations. A hypothesis is outlined that suggests that these all may be part of the same process.     

Endothelial glycocalyx dysfunction in disease: albuminuria and increased microvascular permeability

Appreciation of the glomerular microcirculation as a specialized microcirculatory bed, rather than as an entirely separate entity, affords important insights into both glomerular and systemic microvascular pathophysiology. In this review we compare regulation of permeability in systemic and glomerular microcirculations, focusing particularly on the role of the endothelial glycocalyx, and consider the implications for disease processes. The luminal surface of vascular endothelium throughout the body is covered with endothelial glycocalyx, comprising surface-anchored proteoglycans, supplemented with adsorbed soluble proteoglycans, glycosaminoglycans and plasma constituents. In both continuous and fenestrated microvessels, this endothelial glycocalyx provides resistance to the transcapillary escape of water and macromolecules, acting as an integral component of the multilayered barrier provided by the walls of these microvessels (ie acting in concert with clefts or fenestrae across endothelial cell layers, basement membranes and pericytes). Dysfunction of any of these capillary wall components, including the endothelial glycocalyx, can disrupt normal microvascular permeability. Because of its ubiquitous nature, damage to the endothelial glycocalyx alters the permeability of multiple capillary beds: in the glomerulus this is clinically apparent as albuminuria. Generalized damage to the endothelial glycocalyx can therefore manifest as both albuminuria and increased systemic microvascular permeability. This triad of altered endothelial glycocalyx, albuminuria and increased systemic microvascular permeability occurs in a number of important diseases, such as diabetes, with accumulating evidence for a similar phenomenon in ischaemia-reperfusion injury and infectious disease. The detection of albuminuria therefore has implications for the function of the microcirculation as a whole. The importance of the endothelial glycocalyx for other aspects of vascular function/dysfunction, such as mechanotransduction, leukocyte-endothelial interactions and the development of atherosclerosis, indicate that alterations in the endothelial glycocalyx may also be playing a role in the dysfunction of other organs observed in these disease states.     

Novel concepts in sleep regulation

Knowledge regarding the cellular mechanisms of sleep regulation is accumulating rapidly. In addition to neurones, also non‐neuronal brain cells (astrocytes and microglia) are emerging as potential players. New techniques, particularly optogenetics and designed receptors activated by artificial ligands (DREADD), have provided also sleep research with important additional tools to study the effect of either silencing or activating specific neuronal groups/neuronal networks by opening or shutting ion channels on cells. The advantages of these strategies are the possibility to genetically target specific cell populations and the possibility to either activate or inhibit them with inducing light signal into the brain. Studies probing circuits of NREM and REM sleep regulation, as well as their role in memory consolidation, have been conducted recently. In addition, fundamentally new thoughts and potential mechanisms have been introduced to the field. The role of non‐neuronal tissues in the regulation of many brain functions has become evident. These non‐neuronal cells, particularly astrocytes, integrate large number of neurones, and it has been suggested that one of their functions is to integrate the (neural) activity in larger brain areas—a feature that is one of the prominent features of also the state of sleep.     

The spectrum of rare central nervous system (CNS) tumors with EWSR1‐non‐ETS fusions: experience from three pediatric institutions with review of the literature

The group of CNS mesenchymal (non‐meningothelial) and primary glial/neuronal tumors in association with EWSR1‐non‐ETS rearrangements comprises a growing spectrum of entities, mostly reported in isolation with incomplete molecular profiling. Archival files from three pediatric institutions were queried for unusual cases of pediatric (≤21 years) CNS EWSR1‐rearranged tumors confirmed by at least one molecular technique. Extra‐axial tumors and cases with a diagnosis of Ewing sarcoma (EWSR1‐ETS family fusions) were excluded. Additional studies, including anchored multiplex‐PCR with next‐generation sequencing and DNA methylation profiling, were performed as needed to determine fusion partner status and brain tumor methylation class, respectively. Five cases (median 17 years) were identified (M:F of 3:2). Location was parenchymal (n = 3) and undetermined (n = 2) with topographic distributions including posterior fossa (n = 1), frontal (n = 1), temporal (n = 1), parietal (n = 1) and occipital (n = 1) lobes. Final designation with fusion findings included desmoplastic small round cell tumor (EWSR1‐WT1; n = 1) and tumors of uncertain histogenesis (EWSR1‐CREM, n = 1; EWSR1‐CREB1, n = 1; EWSR1‐PLAGL1, n = 1; and EWSR1‐PATZ1, n = 1). Tumors showed a wide spectrum of morphology and biologic behavior. For EWSR1‐CREM, EWSR1‐PLAGL1 and EWSR1‐PATZ1 tumors, no significant methylation scores were reached in the known brain tumor classes. Available outcome (4/5) was reported as favorable (n = 2) and unfavorable (n = 2) with a median follow‐up of 30 months. In conclusion, we describe five primary EWSR1‐non‐ETS fused CNS tumors exhibiting morphologic and biologic heterogeneity and we highlight the clinical importance of determining specific fusion partners to improve diagnostic accuracy, treatment and monitoring. Larger prospective clinicopathological and molecular studies are needed to determine the prognostic implications of histotypes, anatomical location, fusion partners, breakpoints and methylation profiles in patients with these rare tumors.     

S100P immunostaining identifies a subset of peripheral‐type intrahepatic cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic cholangiocarcinomas

Tsai J‐H, Huang W‐C, Kuo K‐T, Yuan R‐H, Chen Y‐L & Jeng Y‐M
(2012) Histopathology
S100P immunostaining identifies a subset of peripheral‐type intrahepatic cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic cholangiocarcinomas Aims: S100P is a calcium‐binding protein that is frequently expressed in pancreatic adenocarcinoma and perihilar cholangiocarcinoma. The aim of this study was to investigate the pathological significance of the expression of S100P in peripheral intrahepatic cholangiocarcinoma (ICC). Methods and results: Immunohistochemical staining was used to investigate S100P expression in 112 cases of peripheral ICC. The results were compared with those for perihilar and extrahepatic cholangiocarcinomas. Patients with S100P‐positive peripheral ICC were more likely to have elevated serum levels of carcinoembryonic antigen (CEA) and CA19‐9 than those with S100P‐negative peripheral ICCs. All cases of peripheral ICC associated with intrahepatic lithiasis and all cases with intraductal/periductal growth patterns were positive for S100P. S100P‐positive peripheral ICCs were highly associated with ‘bile duct’ morphology rather than cholangiolar differentiation. Nearly all cases of perihilar and extrahepatic cholangiocarcinoma were positive for S100P. Similarly to perihilar and extrahepatic cholangiocarcinomas, S100P‐positive peripheral ICCs showed more frequent expression of CEA and MUC2, and were more likely to be N‐cadherin‐negative, than S100P‐negative cases. Notably, K‐RAS mutations were only detected in S100P‐positive peripheral ICCs, with a frequency similar to that in perihilar and extrahepatic cholangiocarcinomas. Patients with S100P‐positive peripheral ICC were more likely to have poor prognoses than those with S100P‐negative tumours. Conclusions: S100P immunostaining identifies a subset of peripheral ICC that probably originates from larger bile ducts. This subset of peripheral ICCs shares common morphological and molecular features with perihilar and extrahepatic cholangiocarcinomas.     

Rap1 promotes proliferation and migration of vascular smooth muscle cell via the ERK pathway

Background

Rap1 is involved in a multitude of cellular signal transduction pathways, which has extensively been linked to cell proliferation and migration. It has been shown to be important in the regulation of physiological and pathological processes. The present study aims to elucidate its detailed mechanistic in proliferation and migration.

‘I Can’t Keep Up!’: an update on advances in soft tissue pathology occurring after the publication of the 2020 World Health Organization classification of soft tissue and bone tumours

Progress in our understanding of the pathogenesis and diagnosis of soft tissue neoplasia is exceptionally rapid. Although the most recent World Health Organization classification of soft tissue tumours contains many new entities and refinements of older ones, even this comprehensive document is by now incomplete or in need of modification. This review will attempt to summarise the developments in soft tissue pathology that have occurred since 2020, emphasising lesions for which morphology and genetics intersect in a complementary fashion. Novel entities discussed include KMT2A-rearranged sarcoma, PRRX::NCOAx fibroblastic tumours, EWSR1::PATZ1 sarcomas, BRAF-altered infantile fibrosarcoma-like lesions, NUTM1-rearranged colorectal sarcomas, and a variety of interesting giant cell-rich and matrix-producing lesions. In addition, recently described mimics of atypical lipomatous tumour/well-differentiated liposarcoma are covered, as is a wholly new, morphologically defined and genetically confirmed entity, pseudoendocrine sarcoma. Finally, exciting new developments in the use of immunohistochemistry as a surrogate for molecular genetic techniques are discussed.     

Modulation of endothelial permeability by 1‐O‐alkylglycerols

Regulation of endothelial barrier function often occurs through signalling involving phospholipase C activation which produces diacylglycerol (DAG), a lipidic second messenger activator of protein kinase C (PKC). Therefore, modification of lipidic composition of endothelial cell membranes might modify DAG production and, as a result, alter regulation of endothelial permeability. We investigated the in vitro effects of natural 1‐O‐alkylglycerols on porcine aortic endothelial cell permeability to dye‐labelled albumin. [³H]‐1‐O‐alkylglycerols (10 μm ) were substantially incorporated into phosphatidylcholine (6.6%) and phosphatidylethanolamine (4.4%). Stimulation of endothelial cell monolayer with phorbol‐myristate‐acetate or with the calcium ionophore A23187 resulted in a raise in permeability to albumin. Pre‐treatment with 1‐O‐alkylglycerols (10 μm , 24 h) had no effect on basal albumin permeability but totally inhibited the effect of phorbol‐myristate‐acetate, and brought the permeability of A23187‐stimulated endothelial cell monolayers below control. After incubation of cells with [³H]‐1‐O‐alkylglycerols (10 μm , 24 h), we detected the production of the analogue of DAG, and PKC inhibitor, [³H]‐1‐O‐alkyl‐2‐acyl‐glycerol, in resting cells. This production was increased by 58% under A23187 stimulation while phorbol‐myristate‐acetate had no effect. Our data demonstrate that natural 1‐O‐alkylglycerols modify endothelial permeability, and suggest that this effect could be mediated through alteration of lipidic signalling.     

P1PK: a blood group system with an identity crisis

The P1PK blood group system (ISBT no. 003) was previously called the P blood group system, and the number of included antigens has varied over time. The history of the system is complicated and sometimes confusing, since several changes to the nomenclature have been made. Furthermore, the association between the antigens and their genetic home has raised many questions, as well as the long‐standing enigma regarding the molecular mechanism underlying the common P₁ and P₂ phenotypes. Step by step, the biochemical and genetic basis underlying the antigens expressed in this system has been revealed. This review will start with the historical background and continue with the latest findings, answering some of the questions such as why individuals with p phenotype lack not only P^k and P expression, but also P1, and whether the P1 antigens exist on both glycolipids and glycoproteins on the human red blood cells.     

A cytokine‐controlled mechanism for integrated regulation of T‐lymphocyte motility,adhesion and activation

The co‐ordination of T‐cell motility, adhesion and activation remains poorly understood. It is also unclear how these functions are co‐ordinated with external stimuli. Here we unveil a series of molecular interactions in cis at the surface of T lymphocytes with potent effects on motility and adhesion in these cells, and communicating with proliferative responses. These interactions were controlled by the signature cytokines of T helper subsets interleukin‐2 (IL‐2) and IL‐4. Low‐density lipoprotein receptor‐related protein 1 (LRP1) was found to play a key role for T‐cell motility by promoting development of polarized cell shape and cell movement. Endogenous thrombospondin‐1 (TSP‐1) enhanced cell surface expression of LRP1 through CD47. Cell surface expressed LRP1 induced motility and processing of TSP‐1 while inhibiting adhesion to intercellular adhesion molecule 1 and fibronectin. Interleukin‐2, but not IL‐4, stimulated synthesis of TSP‐1 and motility through TSP‐1 and LRP1. Stimulation of the T‐cell receptor (TCR)/CD3 complex inhibited TSP‐1 expression. Inhibitor studies indicated that LRP1 regulated TSP‐1 expression and promoted motility through JAK signalling. This LRP1‐mediated motogenic signalling was connected to CD47/Gi protein signalling and IL‐2‐induced signalling through TSP‐1. The motogenic TSP‐1/LRP1 mechanism antagonized TCR/CD3‐induced T‐cell proliferation. These results indicate that LRP1 in collaboration with TSP‐1 directs a counter‐adhesive and counter‐proliferative motogenic cascade. T cells seem programmed to prioritize movement before adhesion through this cascade. In conclusion, vital decision‐making in T lymphocytes regulating motility, adhesive interactions and proliferation, are integrated through a molecular mechanism connecting different cell surface receptors and their signalling pathways.     

Mutation screening and transmission disequilibrium study of ATP10C in autism

Autism is a complex genetic disorder. Chromosome 15 is of particular interest in this disorder, because of previous reports of individuals with autism with chromosomal abnormalities in the 15q11‐q13 region. Transmission disequilibrium between polymorphisms in this region and autism has been also been reported in some, but not all studies. Recently, a novel maternally expressed gene, ATP10C, was characterized and mapped to the chromosome 15q11‐q13 region, 200 kb distal to UBE3A. It encodes a putative aminophospholipid translocase likely to be involved in the asymmetric distribution of proteins in the cell membrane. Preferential maternal expression has been demonstrated in fibroblasts and brain. Because of its physical location and imprinting pattern, ATP10C was considered to be a candidate gene for chromosome 15‐associated autism. In an effort to find the genes responsible for autism in this chromosomal region, 1.5 kb of the 5′ flanking region, as well as the coding and splicing regions of ATP10C, were screened for sequence variants. Several polymorphic markers including five nonsynonymous SNPs were identified. To investigate transmission disequilibrium between ATP10C and autism, a family‐based association study was conducted for 14 markers in 115 autism trios. No significant transmission disequilibrium was found, suggesting ATP10C is unlikely to contribute strongly to susceptibility to autism in these families. However, due to limited power to detect genes of modest effect, the possible functional role of the nonsynonymous SNPs and the functional implications of the SNPs identified from 5′ flanking region and intron 2 splicing region may be evaluated in further studies. © 2002 Wiley‐Liss, Inc.     

Constitutional LZTR1 mutation presenting with a unilateral vestibular schwannoma in a teenager

Schwannomatosis is a rare neurofibromatosis clinically diagnosed by age‐dependent criteria, with bilateral vestibular schwannoma and/or a constitutional NF2 mutation representing exclusion criteria. Following SMARCB1 germline mutations, constitutional mutations in LZTR1 were discovered. We report on the molecular investigation in a patient presenting at 14 years with a unilateral vestibular schwannoma, ultimately causing blindness and unilateral hearing loss, in the absence of other schwannomas or a positive family history. In DNA derived from frozen tumor tissue, a comprehensive NF2, SMARCB1 and LZTR1 analysis showed an NF2 truncating mutation c.1006_1021delins16; an LZTR1 mutation c.791+1G>A; and a partial 22q deletion including NF2, SMARCB1 and LZTR1. Sequence analysis on peripheral blood derived DNA showed the LZTR1 mutation to be constitutional, but the NF2 mutation and partial 22q deletion were not found, indicating them to be somatic events. RNA‐based targeted analysis confirmed missplicing of LZTR1 intron 8, predicted to result in a premature stop codon. This LZTR1 mutation was paternally inherited. While isolated vestibular schwannoma or NF2 may be considered in a young individual with a unilateral vestibular schwannoma, this report suggests that LZTR1 ‐related schwannomatosis be added to this differential diagnosis.