• IMMUNE NETWORK
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• v.22 no.1
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• pp.2.1-2.22
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• 2022

Targeting immune evasion via immune checkpoint pathways has changed the treatment paradigm in cancer. Since CTLA-4 antibody was first approved in 2011 for treatment of metastatic melanoma, eight immune checkpoint inhibitors (ICIs) centered on PD-1 pathway blockade are approved and currently administered to treat 18 different types of cancers. The first part of the review focuses on the history of CTLA-4 and PD-1 discovery and the preclinical experiments that demonstrated the possibility of anti-CTLA-4 and anti-PD-1 as anti-cancer therapeutics. The approval process of clinical trials and clinical utility of ICIs are described, specifically focusing on non-small cell lung cancer (NSCLC), in which immunotherapies are most actively applied. Additionally, this review covers the combination therapy and novel ICIs currently under investigation in NSCLC. Although ICIs are now key pivotal cancer therapy option in clinical settings, they show inconsistent therapeutic efficacy and limited responsiveness. Thus, newly proposed action mechanism to overcome the limitations of ICIs in a near future are also discussed.

• BMB Reports
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• v.51 no.11
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• pp.572-577
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• 2018

Recent studies showed that the PD-1/PD-L1 checkpoint blockade is a dramatic therapy for melanoma by enhancing antitumor immune activity. Currently, major strategies for the PD-1/PD-L1 blockade have mainly focused on the use of antibodies and compounds. Seeking an alternative approach, others employ endogenous proteins as blocking agents. The extracellular domain of PD-1 (ePD1) includes the binding site with PD-L1. Accordingly, we constructed a PD-1-based recombinantly tailored fusion protein (dFv-ePD1) that consists of bivalent variable fragments (dFv) of an MMP-2/9-targeted antibody and ePD1. The melanoma-binding intensity and antitumor activity were also investigated. We found the intense and selective binding capability of the protein dFv-ePD1 to human melanoma specimens was confirmed by a tissue microarray. In addition, dFv-ePD1 significantly suppressed the migration and invasion of mouse melanoma B16-F1 cells, and displayed cytotoxicity to cancer cells in vitro. Notably, dFv-ePD1 significantly inhibited the growth of mouse melanoma B16-F1 tumor cells in mice and in vivo fluorescence imaging showed that dFv-ePD was gradually accumulated into the B16-F1 tumor. Also the B16-F1 tumor fluorescence intensity at the tumor site was stronger than that of dFv. This study indicates that the recombinant protein dFv-ePD1 has an intensive melanoma-binding capability and exerts potent therapeutic efficacy against melanoma. The novel format of the PD-L1-blocked agent may play an active role in antitumor immunotherapy.

• The Korean Journal of Pain
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• v.13 no.2
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• pp.182-186
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• 2000

Background: Ropivacaine is a new amide local anesthetics, having therapeutic properties similar to those of bupivacaine but less cardiovascular toxicity and motor blockade. The aim of this study was to evaluate the effects of ropivacaine used in stellate ganglion block (SGB) compared with those of lidocaine or bupivacaine. Methods: This prospective and crossover study performed in twenty patients with sudden sensory neural hearing loss. All patients received three times SGB, in the paratracheal approach using 8 ml of 1% lidocaine, 0.2% bupivacaine, and 0.2% ropivacaine respectively without any orders. Onset time and action duration of Horner's syndrome were observed after each SGB. Results: Onset time of ropivacaine was the middle of the three agents; earlier lidocaine and slower bupivacaine. Lidocaine ($3.0{\pm}1.9$ min), bupivacaine ($4.1{\pm}2.9$ min) and ropivacaine ($3.3{\pm}1.3$ min). But there were no significant differences; Action duration of Horner's syndrome of ropivacaine (223.6?105.2 min) was longer than lidocaine ($134.6{\pm}77.3$ min) and shorter than bupivacaine ($241.2{\pm}115.8$ min). There were significant differences in the action duration of each local anesthetics (P<0.05). There was no critical side effects and temporary foreign body sensation was the most common side effect. Conclusions: We conclude that ropivacaine is a good alternative in SGB instead of lidocaine or bupivacaine. Ropivacaine is a long acting local anesthetic similar to those of bupivacaine with wide margin of safety. However, optimal concentration and volume of ropivacaine in SGB should be studied.

• The Journal of Internal Korean Medicine
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• v.25 no.2
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• pp.174-182
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• 2004

Object : This study investigates Jaeumganghwa-tang(JGT) has been used for the purpose of prevention and treatment of allergic inflammatory diseases. This study was to investigate the biological effects of JGT. Methods : Cytotoxcicity and inflammatory cytokines secretion with human mast cells(HMC-1) were examined. HMC-1 cells were stimulated with phorbol l2-myristate 13-acetate (PMA) and calcium ionophore A23l87. JGT by itself had no effect on cytotoxicity of HMC-1. The effects of JGT on the secretion of tumor necrosis factor-alpha(TNF-${\alpha}$) and interleukin(IL)-6 from HMC-1 were evaluated with enzyme-linked immunosorbent assay(ELISA). Result : It was found that JGT inhibited PMA plus A23187-induced TNF-${\alpha}$ and IL-6 secretion. JGT also inhibited the $NF-{\kappa}$B(p50) expression. Conclusion : These results suggest that JGT inhibits the secretion of inflammatory cytokines in HMC-1 cells through blockade of $NF-{\kappa}B$ activation. Taken together, these effects support a role for JGT as a therapeutic agent in treatment of allergic inflammatory diseases such as asthma.

• The Korean Journal of Pain
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• v.14 no.1
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• pp.110-113
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• 2001

In controlling chronic intractable pains, the current therapeutic methods used are exercise, over the counter medication, cognitive-behavioral therapy, opioid medication, neural blockade, operation, etc., spinal cord stimulation being the last resort. Spinal cord stimulation was initiated when Shearly and others clinically tested the Gate control theory of Melzack and Wall. This had triggered the advancement of theoretic research on the mechanism and hardware necessary and has resulted in an accumulation of clinical experiences. This is known to be effective for treating sympathetic pain, arachnoiditis, failed back pain syndrome, radiculopathy, peripheral vascular disease, phantom limb syndrome, post-herpetic neuralgia, peripheral neuropathy, and angina pectoris. This report describes our experience in experimental spinal cord stimulation in patients with simultaneous post-herpetic neuralgia and herniated intervertebral disc. There wasn't any improvement in the post-herpetic neuralgia but the symptoms of a herniated intervertebral disc was much ameliorated. This was quite an unexpected result. The patient's back pain returned when the stimulation stopped.

• The Korean Journal of Pain
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• v.24 no.3
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• pp.154-157
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• 2011

Background: Postherpetic neuralgia (PHN) is usually managed pharmacologically. It is not uncommon for patients with chronic kidney disease (CKD) to suffer from PHN. It is difficult to prescribe a sufficient dose of anticonvulsants for intractable pain because of the decreased glomerular filtration rate. If the neural blockade and pulsed radiofrequency ablation provide only short-term amelioration of pain, spinal cord stimulation (SCS) with a low level of evidence may be used only as a last resort. This study was done to evaluate the efficacy of spinal cord stimulation in the treatment of PHN in patients with CKD. Methods: PHN patients with CKD who needed hemo-dialysis who received insufficient relief of pain over a VAS of 8 regardless of the neuropathic medications were eligible for SCS trial. The follow-up period was at least 2 years after permanent implantation. Results: Eleven patients received percutaneous SCS test trial from Jan 2003 to Dec 2007. Four patients had successfully received a permanent SCS implant with their pain being tolerable at a VAS score of less than 3 along with small doses of neuropathic medications. Conclusions: SCS was helpful in managing tolerable pain levels in some PHN patients with CKD along with tolerable neuropathic medications for over 2 years.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.2
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• pp.193-200
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• 2016

Sertraline, a selective serotonin reuptake inhibitor (SSRI), has been reported to lead to cardiac toxicity even at therapeutic doses including sudden cardiac death and ventricular arrhythmia. And in a SSRI-independent manner, sertraline has been known to inhibit various voltage-dependent channels, which play an important role in regulation of cardiovascular system. In the present study, we investigated the action of sertraline on Kv1.5, which is one of cardiac ion channels. The effect of sertraline on the cloned neuronal rat Kv1.5 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Sertraline reduced Kv1.5 whole-cell currents in a reversible concentration-dependent manner, with an $IC_{50}$ value and a Hill coefficient of $0.71{\mu}M$ and 1.29, respectively. Sertraline accelerated the decay rate of inactivation of Kv1.5 currents without modifying the kinetics of current activation. The inhibition increased steeply between -20 and 0 mV, which corresponded with the voltage range for channel opening. In the voltage range positive to +10 mV, inhibition displayed a weak voltage dependence, consistent with an electrical distance ${\delta}$ of 0.16. Sertraline slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of sertraline, were superimposed. Inhibition of Kv1.5 by sertraline was use-dependent. The present results suggest that sertraline acts on Kv1.5 currents as an open-channel blocker.

• The Korean Journal of Physiology and Pharmacology
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• v.17 no.4
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• pp.307-314
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• 2013

Connective tissue growth factor (CTGF) is a potent pro-fibrotic factor, which is implicated in fibrosis through extracellular matrix (ECM) induction in diabetic cardiovascular complications. It is an important downstream mediator in the fibrotic action of transforming growth factor ${\beta}$ ($TGF{\beta}$) and is potentially induced by hyperglycemia in human vascular smooth muscle cells (VSMCs). Therefore, the goal of this study is to identify the signaling pathways of CTGF effects on ECM accumulation and cell proliferation in VSMCs under hyperglycemia. We found that high glucose stimulated the levels of CTGF mRNA and protein and followed by VSMC proliferation and ECM components accumulation such as collagen type 1, collagen type 3 and fibronectin. By depleting endogenous CTGF we showed that CTGF is indispensable for the cell proliferation and ECM components accumulation in high glucose-stimulated VSMCs. In addition, pretreatment with the MEK1/2 specific inhibitors, PD98059 or U0126 potently inhibited the CTGF production and ECM components accumulation in high glucose-stimulated VSMCs. Furthermore, knockdown with ERK1/2 MAPK siRNA resulted in significantly down regulated of CTGF production, ECM components accumulation and cell proliferation in high glucose-stimulated VSMCs. Finally, ERK1/2 signaling regulated Egr-1 protein expression and treatment with recombinant CTGF reversed the Egr-1 expression in high glucose-induced VSMCs. It is conceivable that ERK1/2 MAPK signaling pathway plays an important role in regulating CTGF expression and suggests that blockade of CTGF through ERK1/2 MAPK signaling may be beneficial for therapeutic target of diabetic cardiovascular complication such as atherosclerosis.

• International Journal of Oral Biology
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• v.41 no.3
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• pp.125-131
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• 2016

The aim of the present study was to develop an animal model for evaluation of temporomandibular (TMJ) nociception under TMJ inflammation. We also investigated the participation of $IL-1{\beta}$ in inflammation-induced TMJ nociception. Experiments were carried out using male Sprague-Dawley rats. Intra-articular injection of 3% formalin was administered to evaluate hyperalgesia 3 days after CFA injection. Intra-articular injection of 3% formalin did not produce nociceptive behavior in normal rats. Although intra-articular injection of 3 doses of CFA produced TMJ inflammation, only 1:3 diluted CFA produced hyperalgesia when formalin was injected intra-articularly 3 days after CFA injection. Co-administration of IL-1 receptor inhibitor with formalin into the TMJ cavity 3 days after CFA injection was performed. Co-administration of IL-1 receptor inhibitor significantly inhibited formalin-induced hyperalgesia in rats with CFA-induced TMJ inflammation. These results suggested that intra-articular injection of formalin produced hyperalgesia under chronic TMJ inflammation. Moreover, $IL-1{\beta}$ plays an important role in TMJ hyperalgesia under chronic inflammation and blockade of $IL-1{\beta}$ is a potential therapeutic target for inflammatory TMJ pain.

• International Journal of Oral Biology
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• v.36 no.3
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• pp.143-148
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• 2011

The present study investigated the role of peripheral P2X receptors in inflammatory pain transmission in the orofacial area in rats. Experiments were carried out on male Sprague-Dawley rats weighing 220 to 280 g. Formalin (5%, 50 ${\mu}L$) and complete Freund's adjuvant (CFA, 25 ${\mu}L$) was applied subcutaneously to the vibrissa pad to produce inflammatory pain. TNP-ATP, a $P2X_{2,2/3,4}$ receptor antagonist, or OX-ATP, a $P2X_7$ receptor antagonist, was then injected subcutaneously at 20 minutes prior to formalin injection. One of the antagonists was administered subcutaneously at three days after CFA injection. The subcutaneous injection of formalin produced a biphasic nociceptive behavioral response. Subcutaneous pretreatment with TNP-ATP (80, 160 or 240 ${\mu}g$) significantly suppressed the number of scratches in the second phase produced by formalin injection. The subcutaneous injection of 50 ${\mu}g$ of OX-ATP also produced significant antinociceptive effects in the second phase. Subcutaneous injections of CFA produced increases in mechanical and thermal hypersensitivity. Both TNP-ATP (480 ${\mu}g$) and OX-ATP (100 ${\mu}g$) produced an attenuation of mechanical hypersensitivity. However, no change was observed in thermal hypersensitivity after the injection of either chemical. These results suggest that the blockade of peripheral P2X receptors is a potential therapeutic approach to the onset of inflammatory pain in the orofacial area.