Publications by authors named "Aya Matsui"

39 Publications

Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma.

Gut 2021 Jan 11. Epub 2021 Jan 11.

Radiation Oncology/Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Boston, Massachusetts, USA

Objective: Intrahepatic cholangiocarcinoma (ICC)-a rare liver malignancy with limited therapeutic options-is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression.

Design: We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems.

Results: PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC.PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.
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http://dx.doi.org/10.1136/gutjnl-2020-322493DOI Listing
January 2021

Transhepatic Direct Approach to the "Limit of the Division of the Hepatic Ducts" Leads to a High R0 Resection Rate in Perihilar Cholangiocarcinoma.

J Gastrointest Surg 2021 Jan 5. Epub 2021 Jan 5.

Faculty of Medicine, Department of Gastroenterological Surgery II, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.

Background: Previous studies have shown that curative resection (R0 resection) was among the most crucial factors for the long-term survival of patients with PHCC. To achieve R0 resection, we performed the transhepatic direct approach and resection on the limits of division of the hepatic ducts. Although a recent report showed that the resection margin (RM) status impacted PHCC patients' survival, it is still unclear whether RM is an important clinical factor.

Objective: To describe a technique of transhepatic direct approach and resection on the limit of division of hepatic ducts, investigate its short-term surgical outcome, and validate whether the radial margin (RM) would have a clinical impact on long-term survival of perihilar cholangiocarcinoma (PHCC) patients.

Methods: Consecutive PHCC patients (n = 211) who had undergone major hepatectomy with extrahepatic bile duct resection, without pancreaticoduodenectomy, in our department were retrospectively evaluated.

Results: R0 resection rate was 92% and 86% for invasive cancer-free and both invasive cancer-free and high-grade dysplasia-free resection, respectively. Overall 5-year survival rate was 46.9%. Univariate analysis showed that preoperative serum carcinoembryonic antigen level (> 7.0 mg/dl), pathological lymph node metastasis, and portal vein invasion were independent risk factors, but R status on both resection margin and bile duct margin was not an independent risk factor for survival.

Conclusion: The transhepatic direct approach to the limits of division of the bile ducts leads to the highest R0 resection rate in the horizontal margin of PHCC. Further examination will be needed to determine the adjuvant therapy for PHCC to improve patient survival.
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http://dx.doi.org/10.1007/s11605-020-04891-1DOI Listing
January 2021

Directed Evolution of a Selective and Sensitive Serotonin Sensor via Machine Learning.

Cell 2020 Dec 16;183(7):1986-2002.e26. Epub 2020 Dec 16.

Departments of Biochemistry and Molecular Medicine, Chemistry, Statistics, Molecular and Cellular Biology, and Physiology and Membrane Biology, the Center for Neuroscience, and Graduate Programs in Molecular, Cellular, and Integrative Physiology, Biochemistry, Molecular, Cellular and Developmental Biology and Neuroscience, University of California, Davis, Davis, CA 95616, USA. Electronic address:

Serotonin plays a central role in cognition and is the target of most pharmaceuticals for psychiatric disorders. Existing drugs have limited efficacy; creation of improved versions will require better understanding of serotonergic circuitry, which has been hampered by our inability to monitor serotonin release and transport with high spatial and temporal resolution. We developed and applied a binding-pocket redesign strategy, guided by machine learning, to create a high-performance, soluble, fluorescent serotonin sensor (iSeroSnFR), enabling optical detection of millisecond-scale serotonin transients. We demonstrate that iSeroSnFR can be used to detect serotonin release in freely behaving mice during fear conditioning, social interaction, and sleep/wake transitions. We also developed a robust assay of serotonin transporter function and modulation by drugs. We expect that both machine-learning-guided binding-pocket redesign and iSeroSnFR will have broad utility for the development of other sensors and in vitro and in vivo serotonin detection, respectively.
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http://dx.doi.org/10.1016/j.cell.2020.11.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025677PMC
December 2020

Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma.

J Immunother Cancer 2020 11;8(2)

Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA

Background And Purpose: Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models.

Basic Procedures: We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20 mg/kg daily-combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer.

Main Findings: Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10-a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes-in murine HCC and in blood of patients with HCC. Using -deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy.

Principal Conclusions: Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.
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http://dx.doi.org/10.1136/jitc-2020-001435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689089PMC
November 2020

Outcomes of limited resection for patients with intraductal papillary mucinous neoplasm of the pancreas: A single-center experience.

Pancreatology 2020 Oct 15;20(7):1399-1405. Epub 2020 Sep 15.

Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, West-7, North-15, Kita-ku, Sapporo, 060-8638, Japan.

Background: /ObjectivesThe aim of this study was to clarify the oncological outcomes of patients with intraductal papillary mucinous neoplasm (IPMN) who underwent limited resection (LR).

Methods: This retrospective study analyzed the data of 110 patients with IPMN. Patients with IPMN without a history of pancreatitis who had neither tumor infiltration nor regional lymph node swelling on imaging findings underwent LR. We assessed the oncological outcomes of LR for patients with IPMN by comparing the surgical outcomes of LR and standard resection.

Results: LR was performed in 50 patients (45.5%), including duodenum-preserving pancreatic head resection (n = 31), middle-pancreatectomy (n = 12), spleen-preserving distal pancreatectomy (n = 3), total parenchymal pancreatectomy (n = 3), and partial resection (n = 1). In the LR group, 18 patients had postoperative complications of Clavien-Dindo classification ≥ IIIa. After histopathological examination, the presence of high-grade dysplasia (HGD) and invasive carcinoma (IC) were observed in nine and three patients, respectively, in the LR group, and eight and 22 patients, respectively, in the standard resection group. There was a significant difference in the histopathological diagnosis of IC between the two groups (p < 0.001). Finally, in the LR group, postoperative recurrences occurred in three patients, and the 5-, 10-, and 15-year disease-specific survival rates were all 97.0%.

Conclusions: For patients with IPMN judged to have no infiltrating lesions based on the detailed imaging examination, LR is acceptable and may be considered as an alternative to standard resection.
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http://dx.doi.org/10.1016/j.pan.2020.09.008DOI Listing
October 2020

Time to Recurrence After Surgical Resection and Survival After Recurrence Among Patients with Perihilar and Distal Cholangiocarcinomas.

Ann Surg Oncol 2020 Oct 3;27(11):4171-4180. Epub 2020 May 3.

Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.

Background: The differences between perihilar cholangiocarcinoma (PHCC) and distal cholangiocarcinoma (DCC) regarding recurrence and the factors that affect recurrence after surgery are unclear. This study aims to investigate the differences in recurrence patterns between patients with PHCC and those with DCC after surgical resection with curative intent. It also investigates the risk factors associated with recurrence and survival thereafter.

Patients And Methods: The postoperative courses of 366 patients with extrahepatic cholangiocarcinomas (EHCCs), including 236 with PHCC and 130 with DCC, who underwent surgical resections were investigated retrospectively.

Results: During follow-up, tumors recurred in 143 (60.6%) patients with PHCC and in 72 (55.4%) patients with DCC. Overall survival (OS) after surgery, recurrence-free survival (RFS), and OS after recurrence were similar for the patients with PHCC and those with DCC. The cumulative probability of recurrence declined 3 years after surgery in the patients with PHCC and those with DCC. A multivariable analysis determined that, among the patients with PHCC and those with DCC, regional lymph node metastasis was a significant risk factor associated with RFS. Ten patients with PHCC and eight patients with DCC with two or fewer sites of recurrence in a single organ underwent resections. A multivariable analysis determined that recurrent tumor resection was an independent prognostic factor associated with OS after recurrence in the patients with PHCC and those with DCC.

Conclusions: Postoperative survival did not differ between the patients with PHCC and those with DCC. Frequent surveillances for recurrence are needed for 3 years after surgical resection of EHCCs. In selected patients, surgery for recurrent EHCCs might be associated with improved outcomes.
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http://dx.doi.org/10.1245/s10434-020-08534-2DOI Listing
October 2020

Dual Programmed Death Receptor-1 and Vascular Endothelial Growth Factor Receptor-2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma.

Hepatology 2020 04 14;71(4):1247-1261. Epub 2019 Oct 14.

Edwin. L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA.

Background And Aims: Activation of the antitumor immune response using programmed death receptor-1 (PD-1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). Combining PD-1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown.

Approach And Results: We recapitulated these clinical outcomes using orthotopic-grafted or induced-murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR-2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti-PD-1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti-PD-1/VEGFR-2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8-positive (CD8 ) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor-associated macrophages and reducing T regulatory cell (Treg) and chemokine (C-C motif) receptor 2-positive monocyte infiltration in HCC tissue. In these models, VEGFR-2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD-ligand 1 expression in HCC cells was induced in a paracrine manner upon anti-VEGFR-2 blockade in endothelial cells in part through interferon-gamma expression. Moreover, we found that VEGFR-2 blockade increased PD-1 expression in tumor-infiltrating CD4 cells. We also found that under anti-PD-1 therapy, CD4 cells promote normalized vessel formation in the face of antiangiogenic therapy with anti-VEGFR-2 antibody.

Conclusions: We show that dual anti-PD-1/VEGFR-2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti-PD-1 therapy-resistant and anti-PD-1 therapy-responsive HCC models.
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http://dx.doi.org/10.1002/hep.30889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000304PMC
April 2020

Cocaine Inhibition of Synaptic Transmission in the Ventral Pallidum Is Pathway-Specific and Mediated by Serotonin.

Cell Rep 2018 06;23(13):3852-3863

Laboratory on Neurobiology of Compulsive Behaviors, Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA-IRP), NIH, Bethesda, MD 20892, USA; Intramural Research Program, National Institute on Drug Abuse (NIDA-IRP), Baltimore, MD 21224, USA; Center on Compulsive Behaviors, Intramural Research Program, NIH, Bethesda, MD 20892, USA. Electronic address:

The ventral pallidum (VP) is part of the basal ganglia circuitry and a target of both direct and indirect pathway projections from the nucleus accumbens. VP is important in cocaine reinforcement, and the firing of VP neurons is modulated in vivo during cocaine self-administration. This modulation of firing is thought to be indirect via cocaine actions on dopamine in the accumbens. Here, we show that cocaine directly inhibits synaptic transmission evoked by selective stimulation of indirect pathway projections to VP neurons. The inhibition is independent of dopamine receptor activation, absent in 5-HT1B knockout mice, and mimicked by a serotonin transporter (SERT) blocker. SERT-expressing neurons in dorsal raphe project to the VP. Optogenetic stimulation of these projections evokes serotonin transients and effectively inhibits GABAergic transmission to VP neurons. This study shows that cocaine increases endogenous serotonin in the VP to suppress synaptic transmission selectively from indirect pathway projections to VP neurons.
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http://dx.doi.org/10.1016/j.celrep.2018.05.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101978PMC
June 2018

Undercover Power of Endocannabinoids: Postsynaptic Ion-Channel Modulator.

Neuron 2017 Mar;93(6):1243-1244

Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA. Electronic address:

In this issue of Neuron, Gantz and Bean (2017) show that the endocannabinoid 2-arachidonoyl glycerol (2-AG) can directly alter the properties of native ion-channel Kv and accelerate the pacemaker activity of rodent dopamine neurons. These findings are one of the first demonstrations of postsynaptic, cell-autonomous actions of endocannabinoids in the mammalian brain.
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http://dx.doi.org/10.1016/j.neuron.2017.03.014DOI Listing
March 2017

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.

Biol Psychiatry 2017 05 26;81(9):778-788. Epub 2016 Dec 26.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch; Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada. Electronic address:

Background: Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward.

Methods: We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in gamma-aminobutyric acidergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology, and microdialysis; probed neuronal activation by c-Fos immunohistochemistry and resting-state functional magnetic resonance imaging; and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food.

Results: Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area, local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, and neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures.

Conclusions: Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus, beyond a well-established role in reward processing, operating at the level of local ventral tegmental area neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors.
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http://dx.doi.org/10.1016/j.biopsych.2016.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386808PMC
May 2017

Endothelial cell transplantation in tumors restores normal vasculature, reduces tumor hypoxia, and suppresses tumor outgrowth.

J Oral Biosci 2016 Nov 10;58(4):150-157. Epub 2016 Jun 10.

Department of Anatomy and Developmental Biology, School of Medicine, Tokyo Women׳s Medical University, Tokyo, Japan.

Objectives: Vascular normalization, or restoration of the normal structure and function of blood vessels, using molecular-targeted therapy, has emerged as a potential strategy for treating malignant cancer and other vascular disorders. We hypothesized that restoring tumor blood vessels to their normal state would alleviate hypoxic conditions and potentially enhance the delivery of anticancer drugs. Our objective was to determine if transplanting normal endothelial cells into tumor-bearing mice could trigger vascular normalization.

Methods: Tumor cells were injected into the dorsal subcutis of severe combined immunodeficiency (SCID) mice (day 0). Tumor-bearing mice were injected intraperitoneally with cisplatin at day 14 to create scaffolds for blood vessel formation in the tumors. At day 28, human microvascular endothelial cells (HMVECs) or human embryonic stem-derived endothelial cells (ESECs) were transplanted into the necrotic regions of the tumor to induce normal angiogenesis.

Results: Microscopic observation revealed that the transplanted HMVECs or ESECs formed anastomoses with the host mouse vasculature. In addition, blood vessels with blood flow could be detected after 14d. Blood vessels reconstituted by HMVECs or ESECs exhibited normal vasculature, and tumor growth was significantly inhibited upon treatment.

Conclusion: Reconstruction of tumor blood vessels to their normal state alleviated hypoxic conditions and improved the efficiency of drug delivery; the present approach provides a useful model for the development of new cancer therapies.
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http://dx.doi.org/10.1016/j.job.2016.05.003DOI Listing
November 2016

Electron microscopic study of capillary network remodeling in the extensor digitorum longus muscle of normal adult rat.

Microscopy (Oxf) 2016 12 21;65(6):508-516. Epub 2016 Sep 21.

Department of Anatomy and Developmental Biology, School of Medicine, Tokyo Women's Medical University, 1628666 Tokyo, Japan

Capillary networks demonstrate structural changes during maturation, aging, vascular disease, and cancer. Their morphological structure and function have an important influence on each other. Understanding the process of morphological vascular changes in the capillary network with advancing age may help overcome fatal vascular diseases. Aging-related structural changes of the capillary segments may accompany degeneration and regeneration of muscle fibers and serve to remodel the capillary network as a means of adapting to the changing environment. However, difficulty in obtaining human samples has hampered clarification of these microstructural changes. Herein, we examined serial ultrathin sections of capillary segments in the extensor digitorum longus muscle of normal mature (12 months old) rats in an attempt to analyze their structural changes. After bifurcation, a minimum of one capillary segment was filled with erythrocytes and was found to have fenestrations and plural endothelial disruptions, or pores, at the fenestrated portions. Some of the stagnated erythrocytes demonstrated extended protrusions, and their processes appeared to penetrate the basal lamina through the pores. These findings can also show that capillary segments are involved in partial remodeling of the capillary network. A better understanding of age-related structural changes of the capillary networks will help in fine-tuning novel vascular therapy for not only several fatal vascular diseases but also malignant tumors.
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http://dx.doi.org/10.1093/jmicro/dfw040DOI Listing
December 2016

Dopamine Regulation of Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of Cocaine.

Neuron 2016 06 12;90(5):1100-13. Epub 2016 May 12.

Section on Neuronal Structure, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA. Electronic address:

Striatal medium spiny neurons (MSNs) form inhibitory synapses on neighboring striatal neurons through axon collaterals. The functional relevance of this lateral inhibition and its regulation by dopamine remains elusive. We show that synchronized stimulation of collateral transmission from multiple indirect-pathway MSNs (iMSNs) potently inhibits action potentials in direct-pathway MSNs (dMSNs) in the nucleus accumbens. Dopamine D2 receptors (D2Rs) suppress lateral inhibition from iMSNs to disinhibit dMSNs, which are known to facilitate locomotion. Surprisingly, D2R inhibition of synaptic transmission was larger at axon collaterals from iMSNs than their projections to the ventral pallidum. Targeted deletion of D2Rs from iMSNs impaired cocaine's ability to suppress lateral inhibition and increase locomotion. These impairments were rescued by chemogenetic activation of Gi-signaling in iMSNs. These findings shed light on the functional significance of lateral inhibition between MSNs and offer a novel synaptic mechanism by which dopamine gates locomotion and cocaine exerts its canonical stimulant response. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2016.04.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891261PMC
June 2016

Oxidative addition of an aromatic ortho C-H bond of tetraphosphine to asymmetric diiridium(i) centres.

Dalton Trans 2016 Mar 10;45(11):4747-61. Epub 2016 Feb 10.

Department of Chemistry, Faculty of Science, Nara Women's University, Kitauoya-nishi-machi, Nara 630-8506, Japan.

Reactions of a tetraphosphine, meso-bis{[(diphenylphosphinomethyl)phenyl]phosphino}propane (dpmppp), with [IrCl(cod)]2 and CO (1 atm) or isocyanide (RNC) in the presence of NH4PF6 at 80-100 °C in dichloromethane/acetonitrile/acetone and/or methanol mixed solvents afforded asymmetric diiridium(ii) complexes, [Ir2(H)(Cl)(μ-(dpmppp-H)-κP(4)C)(CO)3]PF6 (1) and [Ir2(H)(μ-(dpmppp-H)-κP(4)C)(RNC)4)]-(PF6)2 (R = 2,6-xylyl (2), 2,4,6-mesityl (3); dpmppp-H = {PPh(o-C6H4)CH2P(Ph)(CH2)3P(Ph)CH2PPh2}(-)). A similar reaction with (t)BuNC resulted in the formation of a mononuclear Ir(III) complex of [Ir(H)(dpmppp-κP(3))((t)BuNC)2](PF6)2 (4). Complexes 1-3 were characterized by ESI mass spectrometry, (1)H and (31)P NMR spectroscopy and X-ray diffraction analyses. They were found to consist of cis/trans-P,P asymmetric Ir(II)-Ir(II) bonded dinuclear structures derived from oxidative addition of an ortho C-H bond of dpmppp (Ir-Ir = 2.8044(2) Å (1), 2.8569(2) Å (2), and 2.8524(5) Å (3)), resulting in a [IrPCCIr] intermetallic cyclometal-bridge and a terminal hydride. DFT calculations indicated the presence of Ir-Ir, Ir-H, and Ir-Cortho covalent bonds. Initial stages of the reactions with CO and XylNC at room temperature were investigated by (31)P{(1)H} NMR spectroscopy and found to contain a symmetrical Ir(I) dinuclear unit with dpmppp that was readily transformed into 1 and 2 upon heating. The Ir intermediate with XylNC, [Ir2(XylNC)4(μ-dpmppp)](PF6)2 (6), was isolated and characterized by X-ray crystallography and DFT calculations as an electron-deficient 32e(-) Ir species involving a Ir(I)→Ir(I) dative bond (2.7989(5) Å). The reaction pathways from 6 to 2 were investigated by DFT calculations. The present study suggested that a novel oxidative addition of an ortho C-H bond proceeded on the cis/trans-P,P asymmetric diiridium(i) scaffold supported by the tetraphosphine, dpmppp, which was assumed to be facilitated by dimetal cooperation with switching Ir→Ir dative interactions.
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http://dx.doi.org/10.1039/c5dt04725kDOI Listing
March 2016

Separate GABA afferents to dopamine neurons mediate acute action of opioids, development of tolerance, and expression of withdrawal.

Neuron 2014 Jun 22;82(6):1346-56. Epub 2014 May 22.

Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA. Electronic address:

GABA release from interneurons in VTA, projections from the nucleus accumbens (NAc), and rostromedial tegmental nucleus (RMTg) was selectively activated in rat brain slices. The inhibition induced by μ-opioid agonists was pathway dependent. Morphine induced a 46% inhibition of IPSCs evoked from the RMTg, 18% from NAc, and IPSCs evoked from VTA interneurons were almost insensitive (11% inhibition). In vivo morphine treatment resulted in tolerance to the inhibition of RMTg, but not local interneurons or NAc, inputs. One common sign of opioid withdrawal is an increase in adenosine-dependent inhibition. IPSCs evoked from the NAc were potently inhibited by activation of presynaptic adenosine receptors, whereas IPSCs evoked from RMTg were not changed. Blockade of adenosine receptors selectively increased IPSCs evoked from the NAc during morphine withdrawal. Thus, the acute action of opioids, the development of tolerance, and the expression of withdrawal are mediated by separate GABA afferents to dopamine neurons.
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http://dx.doi.org/10.1016/j.neuron.2014.04.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072256PMC
June 2014

Preclinical study of near-infrared-guided sentinel lymph node mapping of the porcine lung.

Ann Thorac Surg 2013 Jan 25;95(1):312-8. Epub 2012 Oct 25.

Division of Thoracic Surgery, Brigham & Women's Hospital, Boston, Massachusetts, USA.

Background: The presence of lymph node metastasis is the most important prognostic factor in early non-small cell lung cancer. Our objective was to develop a rapid, simple, and reliable method for thoracic sentinel lymph node (SLN) identification using near-infrared fluorescence imaging and clinically available contrast agents.

Methods: Indocyanine green (ICG) reconstituted in saline, human serum albumin, human fresh frozen plasma, and autologous porcine plasma was evaluated for optimal formulation and dosing for SLN within porcine lungs. Animals were imaged using the fluorescence-assisted resection and exploration for surgery imaging system. The SLN identification rate, time to identification and fluorescence intensity of the SLN, bronchus, and background were measured.

Results: The SLN identification rates varied widely, ranging from 33% to 100% as a function of the carrier used for ICG reconstitution. No significant difference was noted in SLN fluorescence intensity; however, bronchial intensity was significantly higher with ICG: albumin, which resulted in the lowest rate of SLN identification. Subsequent evaluation with 125 μM and 250 μM ICG:porcine plasma resulted in identification of strongly fluorescent SLNs, with identification rates of 93% and 100% and median signal-to-background ratios of 8.5 and 12.15, respectively, in less than 2 minutes in situ.

Conclusions: Near-infrared fluorescence imaging with ICG is a reliable method for SLN mapping in the lung with high sensitivity. Mixing of ICG with plasma resulted in strong SLN fluorescence signal with reliable identification rates.
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http://dx.doi.org/10.1016/j.athoracsur.2012.08.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600556PMC
January 2013

Potential anti-tumor effect of IFN-λ2 (IL-28A) against human lung cancer cells.

Lung Cancer 2012 Dec 27;78(3):185-92. Epub 2012 Sep 27.

Department of General Thoracic Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.

Interferon (IFN)-λs (IL-28A/IL-28B/IL-29) classified as type III IFNs, are the latest members identified of the interferon family. As with type I IFNs such as IFN-α, type III IFNs share antiviral and antitumor activity and may have fewer side effects due to a more selective receptor distribution. Therefore, type III IFNs may be clinically useful for human viral and malignant diseases. Here we demonstrate the potential anti-tumor effect of IFN-λ2 (IL-28A) against human lung cancer cells. All lung cancer cell lines that we examined expressed both IFN-λ receptors (IL-28R1 and IL-10R2). Lung cancer cells with epidermal growth factor receptor (EGFR) mutations were more sensitive to IFN-λ2 treatment compared with cells with KRAS mutations. HCC827 cells with an EGFR mutation treated with IFN-λ2 underwent growth suppression and apoptotic cell death by STAT1 phosphorylation. Administration of neutralizing antibodies to IFN-λ inhibited caspase-3/7 activity induced by IFN-λ2. Finally, in vivo luminescent imaging also demonstrated the anti-tumor effect of IFN-λ2 in a cancer cell transplant animal model. Taken together, IFN-λ2 would be a new therapeutic agent for clinical lung cancers with EGFR mutations.
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http://dx.doi.org/10.1016/j.lungcan.2012.09.005DOI Listing
December 2012

CXCL17 expression by tumor cells recruits CD11b+Gr1 high F4/80- cells and promotes tumor progression.

PLoS One 2012 29;7(8):e44080. Epub 2012 Aug 29.

Laboratory of Tumor Biology, Takasaki University of Health and Welfare, Takasaki, Gunma, Japan.

Background: Chemokines are involved in multiple aspects of pathogenesis and cellular trafficking in tumorigenesis. In this study, we report that the latest member of the C-X-C-type chemokines, CXCL17 (DMC/VCC-1), recruits immature myeloid-derived cells and enhances early tumor progression.

Methodology/principal Findings: CXCL17 was preferentially expressed in some aggressive types of gastrointestinal, breast, and lung cancer cells. CXCL17 expression did not impart NIH3T3 cells with oncogenic potential in vitro, but CXCL17-expressing NIH3T3 cells could form vasculature-rich tumors in immunodeficient mice. Our data showed that CXCL17-expressing tumor cells increased immature CD11b(+)Gr1(+) myeloid-derived cells at tumor sites in mice and promoted CD31(+) tumor angiogenesis. Extensive chemotactic assays proved that CXCL17-responding cells were CD11b(+)Gr1(high)F4/80(-) cells (≈ 90%) with a neutrophil-like morphology in vitro. Although CXCL17 expression could not increase the number of CD11b(+)Gr1(+) cells in tumor-burdened SCID mice or promote metastases of low metastatic colon cancer cells, the existence of CXCL17-responding myeloid-derived cells caused a striking enhancement of xenograft tumor formation.

Conclusions/significance: These results suggest that aberrant expression of CXCL17 in tumor cells recruits immature myeloid-derived cells and promotes tumor progression through angiogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044080PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430639PMC
February 2013

Effect of host immunity on metastatic potential in renal cell carcinoma: the assessment of optimal in vivo models to study metastatic behavior of renal cancer cells.

Tumour Biol 2012 Apr 5;33(2):551-9. Epub 2012 Jan 5.

Department of Urology, Jichi Medical University, Shimotsuke, Tochigi, Japan.

There has been little information about metastatic behavior of renal cell carcinoma (RCC) cells because human cancers metastasize only rarely in immunodeficient mice. Moreover, it is difficult to know the effect of host immunity on RCC metastasis due to lack of such RCC cells as transplantable in not only xenograft models but also counterparts with intact immunity. Therefore, we scrutinized in vivo metastasis of RCC cells to seek for the optimal preclinical model to study metastatic behavior. The luciferase-expressing three representative human RCC cell lines (Caki-1, A498, and 786-O) and rat ACI-RCC cell which were established in our laboratory were transplanted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice or immunocompetent ACI rats by intracardiac injection as well as orthotopic inoculation. Metastasis was monitored using a bioluminescent imaging technique. Metastasis was rare in the three human RCC cells even when they were directly disseminated into systemic circulation under the condition least susceptible to host immune attack in NOD/SCID mice. In contrast, ACI-RCC cells spontaneously metastasized to pulmonary tissue from orthotopic tumor sites and systemically spread via intracardiac route. Metastases were more extensive when the cells were inoculated into an immunodeficient host, implying suppressive effect of host immunity on colonization of RCC cells. These results suggest that the representative human RCC cells are not adequate resource to study metastasis but that the luciferase-labeled ACI-RCC cell characterized by its luminescent stability, enhanced tumorigenicity, and widespread metastatic potential provides a useful in vivo model for preclinical assessment of cancer progression and potential therapies against RCC.
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http://dx.doi.org/10.1007/s13277-011-0300-4DOI Listing
April 2012

Opioid-sensitive GABA inputs from rostromedial tegmental nucleus synapse onto midbrain dopamine neurons.

J Neurosci 2011 Nov;31(48):17729-35

Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, USA.

Opioids increase dopamine release in the brain through inhibition of GABA-A IPSCs onto dopamine cells. Immunolabeling indicates that GABA neurons in the rostromedial tegmental nucleus (RMTg), also known as the tail of the ventral tegmental area, send a dense projection to midbrain dopamine neurons stain for μ-opioid receptors. There is however, little functional evidence that these neurons play a role in the opioid-dependent increase in dopamine neuron activity. The present study used retrograde tracers injected into the ventral tegmental area and substantia nigra (VTA/SN) to identify RMTg neurons that project to the VTA/SN. Whole-cell current-clamp and cell-attached recordings from labeled RMTg neurons were performed in sagittal slices from rat. The rhythmic spontaneous firing rate of RMTg neurons was decreased and the membrane potential was hyperpolarized in response to application of μ-opioid agonist DAMGO. Agonists that act at κ- and δ-opioid receptors (U69593 and DPDPE) failed to hyperpolarize RMTg neurons. Whole-cell recordings made in dopamine neurons revealed rhythmic, large amplitude spontaneous IPSCs that had a similar frequency, pattern and opioid sensitivity to the firing of RMTg neurons. In addition, electrical and channelrhodopsin-2 stimulation within the RMTg evoked GABA-A IPSCs in dopamine neurons that were inhibited by μ-opioid agonists DAMGO, but not κ- and δ-opioid agonists. Thus, this study demonstrates functional connection from the RMTg to the VTA/SN mediated by a dense, opioid-sensitive GABA innervation, and that the RMTg is a key structure in the μ-opioid receptor-dependent regulation of dopamine neurons.
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http://dx.doi.org/10.1523/JNEUROSCI.4570-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617570PMC
November 2011

Biosynthetic Pathway for Sex Pheromone Components Produced in a Plusiinae Moth, Plusia festucae.

Front Endocrinol (Lausanne) 2011 14;2:74. Epub 2011 Nov 14.

Graduate School of Bio-Applications and Systems Engineering, Tokyo University of Agriculture and Technology Koganei, Tokyo, Japan.

While many Plusiinae species commonly secrete (Z)-7-dodecenyl acetate (Z7-12:OAc) as a key pheromone component, female moths of the rice looper (Plusia festucae) exceptionally utilize (Z)-5-dodecenyl acetate (Z5-12:OAc) to communicate with their partners. GC-MS analysis of methyl esters derived from fatty acids included in the pheromone gland of P. festucae showed a series of esters monounsaturated at the ω7-position, i.e., (Z)-5-dodecenoate, (Z)-7-tetradecenoate, (Z)-9-hexadecenoate (Z9-16:Me), and (Z)-11-octadecenoate (Z11-18:Me). By topical application of D(3)-labled palmitic acid (16:Acid) and stearic acid (18:Acid) to the pheromone glands, similar amounts of D(3)-Z5-12:OAc were detected. The glands treated with D(13)-labeled monoenoic acids (Z9-16:Acid and Z11-18:Acid), which were custom-made by utilizing an acetylene coupling reaction with D(13)-1-bromohexane, also produced similar amounts of D(13)-Z5-12:OAc. These results suggested that Z5-12:OAc was biosynthesized by ω7-desaturase with low substrate specificity, which could introduce a double bond at the 9-position of a 16:Acid derivative and the 11-position of an 18:Acid derivative. Additional experiments with the glands pretreated with an inhibitor of chain elongation supported this speculation. Furthermore, a comparative study with another Plusiinae species (Chrysodeixis eriosoma) secreting Z7-12:OAc indicated that the β-oxidation systems of P. festucae and C. eriosoma were different.
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http://dx.doi.org/10.3389/fendo.2011.00074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355991PMC
August 2012

Rapid translocation of nanoparticles from the lung airspaces to the body.

Nat Biotechnol 2010 Dec 7;28(12):1300-3. Epub 2010 Nov 7.

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

Nano-size particles show promise for pulmonary drug delivery, yet their behavior after deposition in the lung remains poorly understood. In this study, a series of near-infrared (NIR) fluorescent nanoparticles were systematically varied in chemical composition, shape, size and surface charge, and their biodistribution and elimination were quantified in rat models after lung instillation. We demonstrate that nanoparticles with hydrodynamic diameter (HD) less than ≈34 nm and a noncationic surface charge translocate rapidly from the lung to mediastinal lymph nodes. Nanoparticles of HD < 6 nm can traffic rapidly from the lungs to lymph nodes and the bloodstream, and then be subsequently cleared by the kidneys. We discuss the importance of these findings for drug delivery, air pollution and carcinogenesis.
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http://dx.doi.org/10.1038/nbt.1696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058321PMC
December 2010

Predictive capability of near-infrared fluorescence angiography in submental perforator flap survival.

Plast Reconstr Surg 2010 Nov;126(5):1518-1527

Boston, Mass.; and Sapporo, Japan From the Division of Hematology/Oncology, Department of Medicine, the Division of Plastic and Reconstructive Surgery, Department of Surgery, and the Department of Radiology, Beth Israel Deaconess Medical Center; the Division of Cancer Diagnostics and Therapeutics, Hokkaido University Graduate School of Medicine; and the Department of Surgery, Brigham & Women's Hospital.

Background: Perforator flaps have become increasingly popular in reconstructive surgery, as patients experience less donor-site morbidity than with conventional musculocutaneous flaps. Previously, the authors' laboratory described the intraoperative use of near-infrared fluorescence angiography for patient-specific perforator flap design. This study evaluates the predictive capability of near-infrared fluorescence angiography for flap survival in submental flap reconstruction.

Methods: Near-infrared angiography was performed using indocyanine green at 0, 0.5, 24, 48, and 72 hours after surgery for flap creation in 12 pigs. A single perforator artery was preserved during flap creation based on location (central or noncentral) and dominance (dominant or nondominant). Venous drainage, arterial perfusion, and perfused area as a percentage of total flap area were analyzed. Clinical assessments of perfusion were compared with those made using near-infrared imaging and histology.

Results: Use of near-infrared fluorescence angiography immediately after flap creation accurately predicted areas of perfusion at 72 hours (p=0.0013), compared with the initial clinical assessment (p=0.3085). Identification of necrosis by histology at 72 hours correlated with near-infrared findings of insufficient arterial perfusion immediately after flap creation. No statistically significant differences in perfusion metrics were detected based on location or dominance of the preserved perforator; however, flaps containing central perforators had a higher percentage perfused area than those with noncentral perforators.

Conclusions: The use of near-infrared angiography immediately after flap creation can predict areas of perfusion at 72 hours. This predictive capability may permit intraoperative revision of compromised flaps that have a high likelihood of failure.
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http://dx.doi.org/10.1097/PRS.0b013e3181ef8ce7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2974176PMC
November 2010

High hole mobility for a side-chain liquid-crystalline smectic polysiloxane exhibiting a nanosegregated structure with a terthiophene moiety.

Chemistry 2010 Dec;16(45):13465-72

Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

Side-chain liquid-crystalline siloxane polymers bearing terthiophene moieties as mesogenic pendant groups have been synthesized. An alkenylterthiophene derivative was treated with poly(hydrogenmethylsiloxane) and poly(dimethylsiloxane-co-hydrogenmethylsiloxane)s in Me(2)SiO/MeHSiO ratios of 1:1 and 7:3, respectively, in the presence of the Karstedt catalyst, to produce pale yellow polymers. The degrees of introduction of the mesogenic unit were 100, 50, and 30%, respectively. The polymers exhibit ordered smectic phases at room temperature. The copolymers with dimethylsiloxane units form smectic phases as a consequence of nanosegregation between the mesogenic units and siloxane backbones with the alkylene spacers. Time-of-flight measurement reveals that the hole mobility exceeds 1×10(-2) cm(2) V(-1) s(-1) in the ordered smectic phase of the copolymer with a degree introduction of the mesogenic units of 50%. This value is comparable to that of the highly ordered mesophases of low-molecular-weight derivatives of phenylnaphthalene and terthiophene. Because of the segregation behavior induced by the flexible backbone, a closer molecular packing structure favorable for fast carrier transport may be formed in the smectic phase of the copolymer in spite of the low density of the mesogenic groups.
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http://dx.doi.org/10.1002/chem.200902440DOI Listing
December 2010

Activation of µ-opioid receptors and block of Kir3 potassium channels and NMDA receptor conductance by L- and D-methadone in rat locus coeruleus.

Br J Pharmacol 2010 Nov;161(6):1403-13

Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA.

Background And Purpose: Methadone activates opioid receptors to increase a potassium conductance mediated by G-protein-coupled, inwardly rectifying, potassium (K(IR) 3) channels. Methadone also blocks K(IR) 3 channels and N-methyl-D-aspartic acid (NMDA) receptors. However, the concentration dependence and stereospecificity of receptor activation and channel blockade by methadone on single neurons has not been characterized.

Experimental Approach: Intracellular and whole-cell recording were made from locus coeruleus neurons in brain slices and the activation of µ-opioid receptors and blockade of K(IR) 3 and NMDA channels with L- and D-methadone was examined.

Key Results: The potency of L-methadone, measured by the amplitude of hyperpolarization was 16.5-fold higher than with D-methadone. A maximum hyperpolarization was caused by both enantiomers (∼30 mV); however, the maximum outward current measured with whole-cell voltage-clamp recording was smaller than the current induced by [Met](5) enkephalin. The K(IR) 3 conductance induced by activation of α(2) -adrenoceptors was decreased with high concentrations of L- and D-methadone (10-30 µM). In addition, methadone blocked the resting inward rectifying conductance (K(IR) ). Both L- and D-methadone blocked the NMDA receptor-dependent current. The block of NMDA receptor-dependent current was voltage-dependent suggesting that methadone acted as a channel blocker.

Conclusions And Implications: Methadone activated µ-opioid receptors at low concentrations in a stereospecific manner. K(IR) 3 and NMDA receptor channel block was not stereospecific and required substantially higher concentrations. The separation in the concentration range suggests that the activation of µ-opioid receptors rather than the channel blocking properties mediate both the therapeutic and toxic actions of methadone.
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http://dx.doi.org/10.1111/j.1476-5381.2010.00967.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000663PMC
November 2010

Real-time intra-operative near-infrared fluorescence identification of the extrahepatic bile ducts using clinically available contrast agents.

Surgery 2010 Jul 1;148(1):87-95. Epub 2010 Feb 1.

Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

Background: Iatrogenic bile duct injuries are serious complications with patient morbidity. We hypothesized that the invisible near-infrared (NIR) fluorescence properties of methylene blue (MB) and indocyanine green (ICG) could be exploited for real-time, intraoperative imaging of the extrahepatic bile ducts during open and laparoscopic surgeries.

Methods: In all, 2.0 mg/kg of MB and 0.05 mg/kg of ICG were injected intravenously into 35-kg female Yorkshire pigs and the extrahepatic bile ducts were imaged over time using either the Fluorescence-Assisted Resection and Exploration (FLARE) image-guided surgery system (open surgery) or a custom NIR fluorescence laparoscopy system. Surgical anatomy was confirmed using x-ray cholangiography. The contrast-to-background ratio (CBR), contrast-to-liver ratio (CLR), and chemical concentrations in the cystic duct (CD) and common bile duct (CBD) were measured, and the performance of each agent was quantified.

Results: Using NIR fluorescence of MB, the CD and CBD could be identified with good sensitivity (CBR and CLR > or =4), during both open and laparoscopic surgeries, from 10 to 120 min postinjection. Functional impairment of the ducts, including constriction and injury were immediately identifiable. Using NIR fluorescence of ICG, extrahepatic bile ducts did not become visible until 90 min postinjection because of strong residual liver retention; however, between 90 and 240 min, ICG provided exquisitely high sensitivity for both CD and CBD, with CBR > or =8 and CLR > or =4.

Conclusion: We demonstrate that 2 clinically available NIR fluorophores, MB fluorescing at 700 nm and ICG fluorescing at 800 nm, provide sensitive, prolonged identification of the extrahepatic bile ducts and assessment of their functional status.
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http://dx.doi.org/10.1016/j.surg.2009.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886157PMC
July 2010

Real-time, near-infrared, fluorescence-guided identification of the ureters using methylene blue.

Surgery 2010 Jul 1;148(1):78-86. Epub 2010 Feb 1.

Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

Background: The aim of this study was to determine whether the invisible near-infrared (NIR) fluorescence properties of methylene blue (MB), a dye already approved by the U.S. Food and Drug Administration for other indications, could be exploited for real-time, intra-operative identification of the ureters.

Methods: The optical properties of MB were quantified in vitro. Open surgery and laparoscopic NIR fluorescence imaging systems were employed. Yorkshire pigs were injected intravenously with 0.1-mg/kg MB (n = 8), 10-mg furosemide followed by 0.1-mg/kg MB (n = 6), or 0.5-mg/kg MB (n = 6). The contrast-to-background ratio (CBR) of the kidney and ureters, and the MB concentration in the urine, were quantified.

Results: Peak MB absorbance, emission, and intensity in urine occurred at 668 nm, 688 nm, and 20 mumol/L, respectively. After intravenous injection, doses as low as 0.1-mg/kg MB provided prolonged imaging of the ureters, and a dose of 0.5 mg/kg provided statistically significant improvement of CBR. The preinjection of furosemide increased urine volume but did not improve CBR. Laparoscopic identification of the ureter using MB NIR fluorescence was demonstrated.

Conclusion: Ureteral imaging using MB NIR fluorescence provides sensitive, real-time, intra-operative identification of the ureters during open and laparoscopic surgeries.
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http://dx.doi.org/10.1016/j.surg.2009.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886170PMC
July 2010

Intraoperative near-infrared fluorescence imaging in perforator flap reconstruction: current research and early clinical experience.

J Reconstr Microsurg 2010 Jan 21;26(1):59-65. Epub 2009 Dec 21.

Division of Plastic and Reconstructive Surgery, Boston, Massachusetts, USA.

Despite recent advances in perforator flap reconstruction, there can be significant variability in vessel size and location. Although preoperative evaluation may provide valuable information, real-time intraoperative methods have the potential to provide the greatest benefit. Our laboratory has developed the Fluorescence-Assisted Resection and Exploration (FLARE) near-infrared (NIR) fluorescence imaging system for intraoperative visualization of details of the underlying vasculature. The FLARE system uses indocyanine green, a safe and reliable NIR fluorophore already FDA-approved for other indications. The system has been optimized in large-animal models for the identification of perforator size, location, and perfusion and has also been translated to the clinic for use during breast reconstruction after mastectomy. In this article, we review our preclinical and clinical data, as well as literature describing the use of similar NIR fluorescence imaging systems in plastic and reconstructive surgery.
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http://dx.doi.org/10.1055/s-0029-1244805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100538PMC
January 2010

Submental perforator flap design with a near-infrared fluorescence imaging system: the relationship among number of perforators, flap perfusion, and venous drainage.

Plast Reconstr Surg 2009 Oct;124(4):1098-1104

Boston, Mass.; and Sapporo, Japan From the Division of Hematology/Oncology, Department of Medicine, the Division of Plastic and Reconstructive Surgery, Department of Surgery, and the Department of Radiology, Beth Israel Deaconess Medical Center, the Department of Surgery, Brigham & Women's Hospital; and the Division of Cancer Diagnostics and Therapeutics, Hokkaido University Graduate School of Medicine.

Background: The submental flap is a reliable alternative to microsurgical reconstruction of facial deformities, providing an excellent cosmetic match with the contour and color of the face. In this study, the authors evaluated submental flap design by using near-infrared fluorescence angiography to identify perforator arteries. The impact of the number of preserved perforator arteries on flap perfusion and venous drainage was quantified.

Methods: Indocyanine green was injected intravenously into 18 pigs. Three groups of six animals each had one, two, or three perforator arteries preserved. The fluorescence-assisted resection and exploration near-infrared fluorescence imaging system was used for image acquisition. Images were recorded before and after flap creation, and every hour, for 6 hours. The time to maximum perfusion, the drainage ratio (an indicator of venous drainage), and the percentage of perfused flap area were analyzed statistically at each time point.

Results: Flaps with a single dominant perforator artery had an initial mean perfused area of 80 percent, which improved to 97 percent at 6 hours. For flaps with two and three preserved perforator arteries, perfused area at 6 hours was 99.8 percent and 100 percent, respectively. A significant increase was observed in all three metrics as more vessels were preserved. Regardless of the number of perforator arteries preserved, though, all three metrics improved over 6 hours.

Conclusions: Near-infrared fluorescence angiography can reliably identify submental perforator arteries for flap design and can be used to assess flap perfusion and venous drainage in real time. Flap metrics at 6 hours were equivalent when either one or multiple perforator arteries were preserved.
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http://dx.doi.org/10.1097/PRS.0b013e3181b5a44cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935690PMC
October 2009

Image-guided perforator flap design using invisible near-infrared light and validation with x-ray angiography.

Ann Plast Surg 2009 Sep;63(3):327-30

Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

Although perforator flaps mark an important conceptual change in reconstructive surgery, individual perforator vessels show a high degree of variability with respect to anatomic landmarks. We have developed an intraoperative imaging system that simultaneously displays surgical anatomy and otherwise invisible near-infrared images. In 22 adult pigs, perforating vessels were identified within seconds using this optical imaging system and systemic injection of indocyanine green. Perforator flaps were then designed based on these results, and vessel location confirmed by direct visualization and anatomic dissection. Since x-ray angiography remains the gold standard for identification of underlying vessels, conventional x-ray angiography was also performed in 8 pigs to verify the location of perforators. There was full correlation of all the perforators identified among near-infrared fluorescence angiography, x-ray angiography, and anatomic dissection. The technology we describe provides high-sensitivity real-time image guidance throughout perforator dissection, and permits patient-specific flap design.
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http://dx.doi.org/10.1097/SAP.0b013e318193493dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756078PMC
September 2009