Expert perspectives on pathological findings in vasculitis.

Pathological findings are important in the diagnosis of vasculitis. However, due to the rarity of the disease, standard textbooks usually devote only a few pages to this topic, and this makes it difficult for clinicians not specializing in vasculitis to fully understand the pathological findings in vasculitis. To address the paucity of information, we present representative pathological findings in vasculitis classified in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012).

BubR1 insufficiency impairs angiogenesis in aging and in experimental critical limb ischemic mice.

Objectives: Budding uninhibited by benzimidazole-related 1 (BubR1), a cell cycle-related protein, is an essential component of the spindle checkpoint that regulates cell division. Mice in which BubR1 expression is reduced to 10% of the normal level display the phenotypic features of progeria. However, the role of BubR1 in vascular diseases and angiogenesis remains unknown.

Chd2 regulates chromatin for proper gene expression toward differentiation in mouse embryonic stem cells.

Chromatin reorganization is necessary for pluripotent stem cells, including embryonic stem cells (ESCs), to acquire lineage potential. However, it remains unclear how ESCs maintain their characteristic chromatin state for appropriate gene expression upon differentiation. Here, we demonstrate that chromodomain helicase DNA-binding domain 2 (Chd2) is required to maintain the differentiation potential of mouse ESCs.

BUBR1 Insufficiency in Mice Increases their Sensitivity to Oxidative Stress.

Background/aim: Budding uninhibited by benzimidazole-related 1 (BUBR1) plays an important role in the spindle assembly checkpoint to prevent chromosome missegregation and aneuploidy during mitosis. We previously generated mutant mice that express BUBR1 at only 20% of the normal level (BubR1 mice). Here, we examined the effect of low BUBR1 expression on oxidative stress-induced carcinogenesis in mice.

BubR1 Insufficiency Impairs Liver Regeneration in Aged Mice after Hepatectomy through Intercalated Disc Abnormality.

A delay in liver regeneration after partial hepatectomy (PHx) leads to acute liver injury, and such delays are frequently observed in aged patients. BubR1 (budding uninhibited by benzimidazole-related 1) controls chromosome mitotic segregation through the spindle assembly checkpoint, and BubR1 down-regulation promotes aging-associated phenotypes. In this study we investigated the effects of BubR1 insufficiency on liver regeneration in mice.

Activation of Nod1 Signaling Induces Fetal Growth Restriction and Death through Fetal and Maternal Vasculopathy.

Intrauterine fetal growth restriction (IUGR) and death (IUFD) are both serious problems in the perinatal medicine. Fetal vasculopathy is currently considered to account for a pathogenic mechanism of IUGR and IUFD. We previously demonstrated that an innate immune receptor, the nucleotide-binding oligomerization domain-1 (Nod1), contributed to the development of vascular inflammations in mice at postnatal stages.

Peritoneal Dissemination Requires an Sp1-Dependent CXCR4/CXCL12 Signaling Axis and Extracellular Matrix-Directed Spheroid Formation.

Peritonitis carcinomatosa is an advanced and intractable state of gastrointestinal and ovarian cancer, where mechanistic elucidation might enable the development of more effective therapies. Peritoneal dissemination of this type of malignancy has been generally thought to initiate from "milky spots" of primitive lymphoid tissues in the peritoneal cavity. In this study, we offer evidence challenging this idea, based on the finding that tumor implantation and directional dissemination was not required for the presence of milky spots, but rather SCF/CXCL12-expressing niche-like cells located at the border regions of perivascular adipose tissue.

BubR1 insufficiency inhibits neointimal hyperplasia through impaired vascular smooth muscle cell proliferation in mice.

Objective: BubR1, a cell cycle-related protein, is an essential component of the spindle checkpoint that regulates cell division. Mice with BubR1 expression reduced to 10% of the normal level display a phenotype characterized by progeria; however, the involvement of BubR1 in vascular diseases is still unknown. We generated mice in which BubR1 expression was reduced to 20% (BubR1(L/L) mice) of that in wild-type mice (BubR1(+/+)) to investigate the effects of BubR1 on arterial intimal hyperplasia.

Activation of an innate immune receptor, Nod1, accelerates atherogenesis in Apoe-/- mice.

Atherosclerosis is essentially a vascular inflammatory process in the presence of an excess amount of lipid. We have recently reported that oral administration of a nucleotide-binding oligomerization domain (Nod)-1 ligand, FK565, induced vascular inflammation in vivo. No studies, however, have proven the association between Nod1 and atherosclerosis in vivo.

Biological characterization and analysis of metastasis-related genes in cell lines derived from the primary lesion and lymph node metastasis of a squamous cell carcinoma arising in the mandibular gingiva.

Controlling metastatic lesions is an important part of improving cancer prognosis, in addition to controlling the primary lesion. There have been numerous histological studies on primary and metastatic lesions, but little basic research has been performed using cell lines from primary and metastatic lesions belonging to the same patient. In this study, we successfully established a cell line derived from lower gingival carcinoma (WK2) as well as a line derived from secondary cervical lymph node metastasis (WK3F) through primary cultures of tissue from a patient with oral squamous cell carcinoma.

Ex vivo generation of highly purified and activated natural killer cells from human peripheral blood.

Adoptive immunotherapy using natural killer (NK) cells has been a promising treatment for intractable malignancies; however, there remain a number of difficulties with respect to the shortage and limited anticancer potency of the effector cells. We here established a simple feeder-free method to generate purified (>90%) and highly activated NK cells from human peripheral blood-derived mononuclear cells (PBMCs). Among the several parameters, we found that CD3 depletion, high-dose interleukin (IL)-2, and use of a specific culture medium were sufficient to obtain highly purified, expanded (∼200-fold) and activated CD3(-)/CD56(+) NK cells from PBMCs, which we designated zenithal-NK (Z-NK) cells.

Chronic kidney disease is associated with neovascularization and intraplaque hemorrhage in coronary atherosclerosis in elders: results from the Hisayama Study.

There is little information regarding whether patients with chronic kidney disease (CKD) have a high incidence of vulnerable plaques in their coronary arteries. To gain additional evidence on this, we conducted a population-based study by randomly selecting 126 subjects from 844 consecutive autopsies of elderly residents of Hisayama, Japan. We then determined the relationships of CKD with neovascularization and intraplaque hemorrhage in coronary atherosclerosis with the subjects classified into four categories based on their estimated glomerular filtration rate (eGFR).

DVC1-0101 to treat peripheral arterial disease: a Phase I/IIa open-label dose-escalation clinical trial.

We here report the results of a Phase I/IIa open-label four dose-escalation clinical study assessing the safety, tolerability, and possible therapeutic efficacy of a single intramuscular administration of DVC1-0101, a new gene transfer vector based on a nontransmissible recombinant Sendai virus (rSeV) expressing the human fibroblast growth factor-2 (FGF-2) gene (rSeV/dF-hFGF2), in patients with peripheral arterial disease (PAD). Gene transfer was done in 12 limbs of 12 patients with rest pain, and three of them had ischemic ulcer(s). No cardiovascular or other serious adverse events (SAEs) caused by gene transfer were detected in the patients over a 6-month follow-up.

Endogenous cardiac troponin T modulates Ca(2+)-mediated smooth muscle contraction.

Mechanisms linked to actin filaments have long been thought to cooperate in smooth muscle contraction, although key molecules were unclear. We show evidence that cardiac troponin T (cTnT) substantially contributes to Ca(2+)-mediated contraction in a physiological range of cytosolic Ca(2+) concentration ([Ca(2+)](i)). cTnT was detected in various smooth muscles of the aorta, trachea, gut and urinary bladder, including in humans.

Transfection of hypoxia-inducible factor-1 decoy oligodeoxynucleotides suppresses expression of vascular endothelial growth factor in oral squamous cell carcinoma cells.

Vasculature development is thought to be an important aspect in the growth and metastasis of solid tumors. Among the many angiogenic factors produced by tumor cells, vascular endothelial growth factor (VEGF) is considered to play a key role in angiogenic processes. VEGF synthesis is modulated by hypoxia-inducible factor-1 (HIF-1) function within the hypoxic microenvironment of growing cancer tissue.

Obstruction enhances rho-kinase pathway and diminishes protein kinase C pathway in carbachol-induced calcium sensitization in contraction of α-toxin permeabilized guinea pig detrusor smooth muscle.

Aims: We investigated the relative important role of rho kinase (ROK) and protein kinase C (PKC) pathways in carbachol (CCh)-induced Ca(2+) sensitization in α-toxin permeabilized Guinea pig detrusor smooth muscle (DSM) following bladder outlet obstruction (BOO).

Methods: Bladder outlet obstruction was created by placement of a silver jeweler's jump rings loosely round the urethro-vesical junction of Guinea pigs. Sham operated Guinea pig underwent a similar protocol without application of the ring and served as control.

BioKnife, a uPA activity-dependent oncolytic Sendai virus, eliminates pleural spread of malignant mesothelioma via simultaneous stimulation of uPA expression.

Malignant pleural mesothelioma (MPM) is highly intractable and readily spreads throughout the surface of the pleural cavity, and these cells have been shown to express urokinase-type plasminogen activator receptor (uPAR). We here examined the potential of our new and powerful recombinant Sendai virus (rSeV), which shows uPAR-specific cell-to-cell fusion activity (rSeV/dMFct14 (uPA2), named "BioKnife"), for tumor cell killing in two independent orthotopic xenograft models of human. Multicycle treatment using BioKnife resulted in the efficient rescue of these models, in association with tumor-specific fusion and apoptosis.

Pericardial fat pad tissue produces angiogenic factors for healing the bronchial stump.

Maintaining blood flow in and supplying various anti-inflammatory or angiogenic cytokines to the bronchial stump are very important factors involved in its healing. Pericardial fat pad tissue samples surgically obtained from 20 patients were assessed, and their angiogenic ability was investigated. The messenger RNA level of all angiogenic cytokines, including vascular endothelial growth factor, fibroblast growth factor-2 (FGF-2), platelet-derived growth factor-A (PDGF-A), angiopoietin-1 (Ang-1), Ang-2 and hepatocyte growth factor (HGF) were detected in the pericardial fat pad tissue.

Antagonism of VEGF by genetically engineered dendritic cells is essential to induce antitumor immunity against malignant ascites.

Malignant ascitis (MA) is a highly intractable and immunotherapy-resistant state of advanced gastrointestinal and ovarian cancers. Using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A/vascular permeability factor and its decoy receptor, soluble fms-like tryrosine kinase receptor-1 (sFLT-1), was a major cause of MA resistance to dendritic cell (DC)-based immunotherapy. We found that the ratio of VEGF-A/sFLT-1 was increased not only in murine but also in human MA, and F-gene-deleted recombinant Sendai virus (rSeV/dF)-mediated secretion of human sFLT-1 by DCs augmented not only the activity of DCs themselves, but also dramatically improved the survival of tumor-bearing animals associated with enhanced CTL activity and its infiltration to peritoneal tumors.

Angiogenic and lymphangiogenic cascades in the tumor microenvironment.

Blood and lymphatic vessels in tumor tissue are major components of the tumor microenvironment. These vessels are newly formed from pre-existing host vessels stimulated by pro-blood-angiogenic and pro-lymph-angiogenic (pro-blood/lymph-angiogenic) factors expressed in tumor cells. Tumor cells establish a specific stromal microenvironment fostering tumor growth, in which blood/lymph-angiogenesis are involved.

High podoplanin expression in cancer cells predicts lower incidence of nodal metastasis in patients with lung squamous cell carcinoma.

Podoplanin is expressed in a variety of malignant cells, and is generally regarded as a factor promoting tumor progression in conventional studies. Conversely, a recent clinicopathological study has revealed that low podoplanin in cancer cells was correlated with poor prognosis of patients with stage IB lung squamous cell carcinoma (LSCC). We here evaluated the clinicopathological relationship between cancer-cell podoplanin expression and clinicopathological parameters in 40 cases of LSCC (stage I-III).

Podoplanin in cancer cells is experimentally able to attenuate prolymphangiogenic and lymphogenous metastatic potentials of lung squamoid cancer cells.

Background: Podoplanin, a mucin-like transmembrane glycoprotein, is reportedly expressed in a variety of malignant cells and is generally regarded as a factor for promoting tumor progression in conventional studies. By contrast, a clinicopathologically conflicting role for podoplanin, namely as a favorable prognostic factor for patients with lung/cervical squamous cell carcinoma (SCC), has recently been reported. Here, we investigated the role of podoplanin expressed in lung squamoid cancer cells (LSCCs) in experimental tumor progression.