The phenotype of infiltrating macrophages influences arteriosclerotic plaque vulnerability in the carotid artery

Background: Proinflammatory (M1) macrophages and anti-inflammatory (M2) macrophages have been identified in atherosclerotic plaques. While these macrophages have been speculated to be related to plaque vulnerability, there are limited studies investigating this relationship. Therefore, we examined the association between macrophage phenotype (M1 versus M2) and plaque vulnerability and clinical events. Methods: Patients undergoing carotid endarterectomy received an ultrasound of the carotid artery before surgery. Plaques were processed for analysis by immunohistochemistry, Western blotting, and real-time polymerase chain reaction studies. Medical history and clinical data were obtained from medical records. Results: Patients were divided into 2 groups: those suffering from acute ischemic attack (symptomatic, n = 31) and those that did not present with symptoms (asymptomatic, n = 34). Ultrasound analysis revealed that plaque vulnerability was greater in the symptomatic group (P= .033; Chi-square test). Immunohistochemistry revealed that plaques from the symptomatic group had a greater concentration of M1 macrophages (CD68-, CD11c-positive) while plaques from the asymptomatic group had more M2 macrophages (CD163-positive). This observation was confirmed by Western blotting. Characterization by real-time polymerase chain reaction studies revealed that plaques from the symptomatic group had increased expression of the M1 markers CD68 and CD11c, as well as monocyte chemoattractive protein-1, interleukin-6, and matrix metalloproteinase-9. In addition, more M1 macrophages expressed in unstable plaques were defined by ultrasound analysis, while more M2 macrophages were expressed in stable plaques. Conclusions: Our data show that M1 macrophage content of atherosclerotic plaques is associated with clinical incidence of ischemic stroke and increased inflammation or fibrinolysis. We also show the benefits of using ultrasound to evaluate vulnerability in the plaques

肺癌におけるREG Iα遺伝子の発現は、腺癌、肩平上皮癌で異なったメカニズムにより、予後不良を示唆する。

The aim of the present study was to evaluate the effects of the REG Iα and REG Iβ genes on lung cancer cell lines, and thereafter, the expression of REG family genes (REG Iα, REG Iβ, REG III, HIP/PAP and REG IV) in lung cancer in relation to patient prognosis was evaluated. Lung adenocarcinoma (AD) and squamous cell carcinoma (SCC) cell lines expressing REG Iα or REG Iβ (HLC-1 REG Iα/Iβ and EBC-1 REG Iα/Iβ) were established, and cell number, cell invasive activity, and anchorage-independent cell growth were compared with these variables in the control cells. The expression levels of REG family genes were evaluated by real-time RT-PCR in surgically resected lung cancers, and disease-specific survival (DSS) curves were generated. The HLC-1 REG Iα/Iβ cell line showed significant increases in cell number and anchorage-independent cell growth compared with the control cells. EBC-1 REG Iα/Iβ cells showed significant increases in cell invasive activity and anchorage-independent cell growth as compared with the control cells. Except for the REG Iβ gene, expression of other REG family genes was observed in the surgically resected samples; however, DSS was significantly worse only in stage I patients who were positive for REG Iα expression than in patients who were negative for REG Iα expression. The effects of REG Iα on AD and SCC cells were different in the in vitro study, and a correlation between REG Iα expression and patient prognosis was noted in the in vivo study. Therefore, overexpression of REG Iα is a risk factor for poor prognosis caused by discrete mechanisms in AD and SCC patients.博士（医学）・乙第1339号・平成26年5月28日本文のリンク：http://dx.doi.org/10.3892/or.2013.2739Copyright © Spandidos Publications 201

A pure invasive micropapillary carcinoma of the pancreatic head: Long disease-free survival after pancreatoduodenectomy and adjuvant chemotherapy with gemcitabine [4]

金沢大学医学部附属病院肝胆膵・移植外科

Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis

Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation1−3. The genetic basis for CIPA is unknown. Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons4. Mice lacking the gene for TrkA, a receptor tyrosine kinase for NGF5,6, share dramatic phenotypic features of CIPA, including loss of responses to painful stimuli, although anhidrosis is not apparent in these animals7. We therefore considered the human TRKA homologue as a candidate for the CIPA gene. The mRNA and genomic DNA encoding TRKA were analysed in three unrelated CIPA patients who had consanguineous parents. We detected a deletion-, splice- and missense-muta-tion in the tyrosine kinase domain in these three patients. Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF−TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans. These results also implicate genes encoding other TRK and neurotrophin family members as candidates for developmental defect(s) of the nervous system

Increased E-selectin in hepatic ischemia-reperfusion injury mediates liver metastasis of pancreatic cancer

金沢大学医薬保健研究域医学系Several recent studies have reported that selectins are produced during ischemia-reperfusion injury, and that selectin ligands play an important role in cell binding to the endothelium and in liver metastasis. Portal clamping during pancreaticoduodenectomy with vessel resection for pancreatic head cancer causes hepatic ischemia-reperfusion injury, which might promote liver metastasis. We investigated the liver colonization of pancreatic cancer cells under hepatic ischemia-reperfusion and examined the involvement of E-selectin and its ligands. A human pancreatic cancer cell line (Capan-1) was injected into the spleen of mice after hepatic ischemia-reperfusion (I/R group). In addition, to investigate the effect of an anti-E-selectin antibody on liver colonization in the IR group, mice received an intraperitoneal injection of the anti-E-selectin antibody following hepatic ischemia-reperfusion and tumor inoculation (IR+Ab group). Four weeks later, mice were sacrificed and the number of tumor nodules on the liver was compared to mice without hepatic ischemia-reperfusion (control group). The incidence of liver metastasis in the I/R group was significantly higher (16 of 20, 80%) than that in the control group (6 of 20, 30%) (P<0.01). Moreover, mice in the I/R group had significantly more tumor nodules compared to those in the control group (median, 9.9 vs. 2.7 nodules) (P<0.01). In the I/R+Ab group, only 2 of 5 (40%) mice developed liver metastases. RT-PCR and southern blotting of the liver extracts showed that the expression of IL-1 and E-selectin mRNA after hepatic ischemia-reperfusion was significantly higher than the basal levels. Hepatic ischemia-reperfusion increases liver metastases and E-selectin expression in pancreatic cancer. These results suggest that E-selectin produced due to hepatic ischemia-reperfusion is involved in liver metastasis.Embargo Period 6 month

Initial ‘TTP Map-Defect’ of Computed Tomography Perfusion as a Predictor of Hemorrhagic Transformation of Acute Ischemic Stroke

Background: Hemorrhagic transformation (HT) following acute ischemic stroke is a major problem, especially for the indication of reperfusion therapy including intravenous administration of recombinant tissue plasminogen activator (IV rt-PA). The specific predictive factors of HT have not yet been established. The present study evaluated the findings of computed tomography perfusion (CTP) images as predictors of subsequent HT to identify patients with low HT risk for reperfusion therapy such as IV rt-PA. Methods: We retrospectively reviewed 68 consecutive stroke patients (41 males; mean age 72.9 years) with steno-occlusive lesions in the major trunk, including 10 patients who underwent IV rt-PA. Each HT was detected on a follow-up T2*-weighted magnetic resonance image until 2 weeks after stroke onset and categorized into four groups [hemorrhagic infarction (HI) type 1 and 2, and parenchymal hematoma (PH) type 1 and 2] according to the European Cooperative Acute Stroke Study (ECASS) classification. We assessed clinical features and radiological findings between the HT and non-HT groups or the PH2 and non-PH2 groups. The efficacy of initial time to peak (TTP) mapping of CTP for predicting HT or PH2 was evaluated. Results: Thirty-four patients (50%) developed subsequent HT: 18 (52.9%) had HI and 16 (47.1%) had PH, including 9 PH2 patients (13.2%). IV rt-PA was not significantly associated with HT or PH2 occurrence. Forty of the 68 patients (59%) revealed defect areas on the initial TTP mapping (TTP map-defect), and 34 of these 40 patients (85%) developed secondary HT and 9 patients (22.5%) developed PH2. Initial ‘TTP map-defect’ was significantly associated with the occurrence of HT (p Conclusions: Initial ‘TTP map-defect’ of CTP could accurately predict HT risk including PH2 risk and identify low-risk patients even in the delayed period