Anti-Melanogenic Effects of Ethanol Extracts of the Leaves and Roots of Patrinia villosa (Thunb.) Juss through Their Inhibition of CREB and Induction of ERK and Autophagy.

Patrinia villosa (Thunb.) Juss is a traditional herb commonly used in East Asia including Korea, Japan, and China. It has been administered to reduce and treat inflammation in Donguibogam, Korea. The mechanism for its anti-inflammatory effects has already been reported. In this study, we confirmed the efficacy of Patrinia villosa (Thunb.) Juss ethanol extract (Pv-EE) for inducing autophagy and investigate its anti-melanogenic properties. Melanin secretion and content were investigated using cells from the melanoma cell line B16F10. Pv-EE inhibited melanin in melanogenesis induced by α-melanocyte-stimulating hormone (α-MSH). The mechanism of inhibition of Pv-EE was confirmed by suppressing the mRNA of microphthalmia-associated transcription factor (MITF), decreasing the phosphorylation level of CREB, and increasing the phosphorylation of ERK. Finally, it was confirmed that Pv-EE induces autophagy through the autophagy markers LC3B and p62, and that the anti-melanogenic effect of Pv-EE is inhibited by the autophagy inhibitor 3-methyl adenine (3-MA). These results suggest that Pv-EE may be used as a skin protectant due to its anti-melanin properties including autophagy.

Optimization of Medial Forebrain Bundle Stimulation Parameters for Operant Conditioning of Rats.

BACKGROUND: The medial forebrain bundle (MFB) is involved in the integration of pleasure and reward. Previous studies have used various stimulation parameters for operant conditioning, though the effectiveness of these parameters has not been systematically studied. OBJECTIVES: The purpose of the present study was to investigate the optimal MFB stimulation parameters for controlling the conditioned behavior of rats. METHODS: We evaluated four factors, including intensity, frequency, pulse duration, and train duration, to determine the effect of each on lever pressure applied by animals. We further compared burst and tonic stimulation in terms of learning and performance abilities. RESULTS: The number of lever presses increased with each factor. Animals in the burst stimulation group exhibited more lever presses. Furthermore, the average speed in the maze among burst stimulation group subjects was higher. CONCLUSION: We determined the optimal parameters for movement control of animals in operant conditioning and locomotor tasks by adjusting various electrical stimulation parameters. Our results reveal that a burst stimulation is more effective than a tonic stimulation for increasing the moving speed and number of lever presses. The use of this stimulation technique also allowed us to minimize the training required to control animal behavior.

Low-Affinity Zinc Sensor Showing Fluorescence Responses with Minimal Artifacts.

The study of the zinc biology requires molecular probes with proper zinc affinity. We developed a low-affinity zinc probe (HBO-ACR) based on an azacrown ether (ACR) and an 2-(2-hydroxyphenyl)benzoxazole (HBO) fluorophore. This probe design imposed positive charge in the vicinity of a zinc coordination center, which enabled fluorescence turn-on responses to high levels of zinc without being affected by the pH and the presence of other transition-metal ions. Steady-state and transient photophysical investigations suggested that such a high tolerance benefits from orchestrated actions of proton-induced nonradiative and zinc-induced radiative control. The zinc bioimaging utility of HBO-ACR has been fully demonstrated with the use of human pancreas epidermoid carcinoma, PANC-1 cells, and rodent hippocampal neurons from cultures and acute brain slices. The results obtained through our studies established the validity of incorporating positively charged ionophores for the creation of low-affinity probes for the visualization of biometals.

An epigenomic signature of postprandial hyperglycemia in peripheral blood leukocytes.

Postprandial hyperglycemia is known to be one of the earliest signs of abnormal glucose homeostasis associated with type 2 diabetes. This study aimed to assess clinical significance of a 1-h postprandial glucose level for the development of diabetes, and identify epigenetic biomarkers of postprandial hyperglycemia. We analyzed clinical data from the oral glucose tolerance tests for healthy subjects (n=4502). The ratio (Glu60/Glu0) of 1-h glucose levels to fasting glucose levels was significantly associated with an insulin sensitive index (QUICKI, quantitative insulin sensitivity check index) (ß=0.055, P=1.25E-04) as well as a risk of future pre-diabetic and diabetic conversion. Next, DNA methylation profile analyses of 24 matched pairs of the high and low Glu60/Glu0 ratio subjects showed that specific DNA methylation levels in the promoter region of an olfactory receptor gene (olfactory receptor gene family10 member A4, OR10A4) were associated with the Glu60/Glu0 ratios (ß=0.337, P=0.03). Moreover, acute oral glucose challenges decreased the DNA methylation levels of OR10A4 but not the global DNA methylation in peripheral leukocytes of healthy subjects (n=7), indicating that OR10A4 is a specific epigenomic target of postprandial hyperglycemia. This work suggests possible relevance of olfactory receptor genes to an earlier molecular biomarker of peripheral hyperglycemia and diabetic conversion.

Amygdala electrical stimulation for operant conditioning in rat navigation.

There have been several attempts to navigate the locomotion of animals by neuromodulation. The most common method is animal training with electrical brain stimulation for directional cues and rewards; the basic principle is to activate dopamine-mediated neural reward pathways such as the medial forebrain bundle (MFB) when the animal correctly follows the external commands. In this study, the amygdala, which is the brain region responsible for fear modulation, was targeted for punishment training. The brain regions of MFB, amygdala, and barrel cortex were electrically stimulated for reward, punishment, and directional cues, respectively. Electrical stimulation was applied to the amygdala of rats when they failed to follow directional commands. First, two different amygdala regions, i.e., basolateral amygdala (BLA) and central amygdala (CeA), were stimulated and compared in terms of behavior responses, success and correction rates for training, and gene expression for learning and memory. Then, the training was performed in three groups: group R (MFB stimulation for reward), group P (BLA stimulation for punishment), and group RP (both MFB and BLA stimulation for reward and punishment). In group P, after the training, RNA sequencing was conducted to detect gene expression and demonstrate the effect of punishment learning. Group P showed higher success rates than group R, and group RP exhibited the most effective locomotion control among the three groups. Gene expression results imply that BLA stimulation can be more effective as a punishment in the learning process than CeA stimulation. We developed a new method to navigate rat locomotion behaviors by applying amygdala stimulation.

Somatosensory ECoG-based brain-machine interface with electrical stimulation on medial forebrain bundle.

Brain-machine interface (BMI) provides an alternative route for controlling an external device with one's intention. For individuals with motor-related disability, the BMI technologies can be used to replace or restore motor functions. Therefore, BMIs for movement restoration generally decode the neural activity from the motor-related brain regions. In this study, however, we designed a BMI system that uses sensory-related neural signals for BMI combined with electrical stimulation for reward. Four-channel electrocorticographic (ECoG) signals were recorded from the whisker-related somatosensory cortex of rats and converted to extract the BMI signals to control the one-dimensional movement of a dot on the screen. At the same time, we used operant conditioning with electrical stimulation on medial forebrain bundle (MFB), which provides a virtual reward to motivate the rat to move the dot towards the desired center region. The BMI task training was performed for 7 days with ECoG recording and MFB stimulation. Animals successfully learned to move the dot location to the desired position using S1BF neural activity. This study successfully demonstrated that it is feasible to utilize the neural signals from the whisker somatosensory cortex for BMI system. In addition, the MFB electrical stimulation is effective for rats to learn the behavioral task for BMI.

Cortical astrocytes modulate dominance behavior in male mice by regulating synaptic excitatory and inhibitory balance.

Social hierarchy is established as an outcome of individual social behaviors, such as dominance behavior during long-term interactions with others. Astrocytes are implicated in optimizing the balance between excitatory and inhibitory (E/I) neuronal activity, which may influence social behavior. However, the contribution of astrocytes in the prefrontal cortex to dominance behavior is unclear. Here we show that dorsomedial prefrontal cortical (dmPFC) astrocytes modulate E/I balance and dominance behavior in adult male mice using in vivo fiber photometry and two-photon microscopy. Optogenetic and chemogenetic activation or inhibition of dmPFC astrocytes show that astrocytes bidirectionally control male mouse dominance behavior, affecting social rank. Dominant and subordinate male mice present distinct prefrontal synaptic E/I balance, regulated by astrocyte activity. Mechanistically, we show that dmPFC astrocytes control cortical E/I balance by simultaneously enhancing presynaptic-excitatory and reducing postsynaptic-inhibitory transmission via astrocyte-derived glutamate and ATP release, respectively. Our findings show how dmPFC astrocyte-neuron communication can be involved in the establishment of social hierarchy in adult male mice.

Expression of SPRR3 is associated with tumor cell proliferation in less advanced stages of breast cancer.

Small proline rich repeat protein 3 (SPRR3), a member of the SPRR family of cornified envelope precursor proteins, is a marker for terminal squamous cell differentiation. Previously, this laboratory showed that SPRR3 is strongly upregulated in colorectal tumors, and is involved in the tumorigenesis. The current study was performed to investigate the expression status and effect of SPRR3 in breast cancers (BCs). SPRR3 expression was examined by immunohistochemistry in 241 tumor samples from BC patients. SPRR3 was overexpressed in more than half of all BC samples. SPRR3 overexpression was significantly associated with less advanced stage (0-1 vs. II-III) and the absence of lymph node metastasis (P = 0.004 and 0.013, respectively). HER2/neu overexpression was closely correlated with SPRR3 overexpression in a multivariate analysis (OR, 3.23, P = 0.017). To assess the influence of SPRR3 on cell proliferation and related signaling pathways, SPRR3-transfected clones from the SPRR3-negative T-47D human BC cell line were generated. Among the total of six SPRR3-overexpressing clones, five showed marked proliferation compared with SPRR3-nonexpressing control cells from day 3 of culture (P < 0.001). The SPRR3-overexpressing BC clones showed increased phosphorylation of AKT and MDM2, p21 overexpression, and p53 downregulation. Furthermore, phosphorylation of MEK and MAPK was markedly increased. This study demonstrates that SPRR3 promotes BC cell proliferation by enhancing p53 degradation via the AKT and MAPK pathways and is, therefore, a potential novel therapeutic target for less advanced stages of BC.

Optrode Array for Simultaneous Optogenetic Modulation and Electrical Neural Recording.

During the last decade, optogenetics has become an essential tool for the investigation of neural signaling due to its unique capability of selective neural modulation or monitoring. As specific types of neuronal cells can be genetically modified to express opsin proteins, optogenetics enables optical stimulation or inhibition of the selected neurons. There have been several technological advances in the optical system for optogenetics. Recently, it was proposed to combine the optical waveguide for light delivery with electrophysiological recording to simultaneously monitor the neural responses to optogenetic stimulation or inhibition. In this study, an implantable optrode array (2x2 optical fibers) was developed with embedded multichannel electrodes. A light-emitting diode (LED) was employed as a light source, and a microfabricated microlens array was integrated to provide sufficient light power at the tip of the optical fibers. The optrode array system comprises the disposable part and the reusable part. The disposable part has optical fibers and electrodes, while the reusable part has the LED and electronic circuitry for light control and neural signal processing. The novel design of the implantable optrode array system is introduced in the accompanying video in addition to the procedure of the optrode implantation surgery, optogenetic light stimulation, and the electrophysiological neural recording. The results of in vivo experiments successfully showed time-locked neural spikes evoked by the light stimuli from hippocampal excitatory neurons of mice.

Two-year clinical outcomes of patients with long segments drug-eluting stents: comparison of sirolimus-eluting stent with paclitaxel-eluting stent.

Limited data are available on the long-term clinical efficacy of drug-eluting stent (DES) in diffuse long lesions. From May 2006 to May 2007, a total of 335 consecutive patients (374 lesions) were underwent percutaneous coronary intervention with implantation of long DES (≥ 30 mm) in real world practice. Eight-month angiographic outcomes and 2-yr clinical outcomes were compared between SES (n = 218) and PES (n = 117). Study endpoints were major adverse cardiac events including cardiac death, myocardial infarction, target-lesion revascularization, target-vessel revascularization and stent thrombosis. Baseline characteristics were similar in the two groups as were mean stent length (44.9 ± 15.2 mm in SES and 47.4 ± 15.9 in PES, P = 0.121). Late loss at 8 months follow-up was significantly lower in SES than in PES group (0.4 ± 0.6 mm in SES vs 0.7 ± 0.8 mm in PES, P = 0.007). Mean follow-up duration was 849 ± 256 days, and 2-yr cumulative major adverse cardiac events were significantly lower in the SES than in the PES group (5.5% in SES vs 15.4% in PES, P = 0.003). In conclusion, long-term DES use in diffuse long coronary lesions is associated with favorable results, with SES being more effective and safer than PES in this real-world clinical experience.

Implantable Optrode Array for Optogenetic Modulation and Electrical Neural Recording.

During the last decade, optogenetics has become an essential tool for neuroscience research due to its unrivaled feature of cell-type-specific neuromodulation. There have been several technological advances in light delivery devices. Among them, the combination of optogenetics and electrophysiology provides an opportunity for facilitating optogenetic approaches. In this study, a novel design of an optrode array was proposed for realizing optical modulation and electrophysiological recording. A 4 × 4 optrode array and five-channel recording electrodes were assembled as a disposable part, while a reusable part comprised an LED (light-emitting diode) source and a power line. After the characterization of the intensity of the light delivered at the fiber tips, in vivo animal experiment was performed with transgenic mice expressing channelrhodopsin, showing the effectiveness of optical activation and neural recording.

Molecular and Serological Investigation of Severe Fever with Thrombocytopenia Syndrome Virus in Cats.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne zoonosis in China, the Republic of Korea (ROK), and Japan. The presence of the SFTS virus (SFTSV) in companion, livestock, and wild animals has been reported. Recently, human SFTS-like clinical symptoms in cats and cheetahs have been reported in Japan. Therefore, the prevalence of the SFTSV gene or antibody in cats is important for public health as well as veterinary medicine. Materials and Methods: Sera were collected from 201 feral and house cats in the ROK in 2017. Samples were analyzed for the presence of the SFTSV gene after RT-nested PCR amplification and for anti-SFTSV antibodies after enzyme linked immunosorbent assay. Results: Eight (4.0%) and nine (4.5%) of 201 cat sera were found to be positive for the SFTSV gene and anti-SFTSV nucleocapsid protein antibodies, respectively. Specifically, 5.9% feral and 2.0% house cats were positive for the SFTSV gene, and 6.9% feral and 2.0% house cats were positive for anti-SFTSV antibodies. All sequences of the SFTSV S segment obtained were included in Japanese/Korean SFTSV clades, as opposed to the Chinese clade. Conclusions: This study constitutes the first serological study of SFTSV in house and feral cats in the ROK. Evidence of SFTSV in companion animals indicates that SFTSV can circulate in homes and that more intensive precautions and education measures are needed for companion animal guardians and veterinarians.

Clinical Potential of Circulating Tumor Cells in Colorectal Cancer: A Prospective Study.

OBJECTIVES: Circulating tumor cells (CTCs) in the blood have been used as diagnostic markers in patients with colorectal cancer (CRC). In this study, we evaluated a CTC detection system based on cell size to assess CTCs and their potential as early diagnostic and prognostic biomarkers for CRC. METHODS: From 2014 to 2015, 88 patients with newly diagnosed CRC, who were scheduled for surgery, and 31 healthy volunteers were enrolled and followed up in Pusan National University Hospital. CTCs were enriched using a centrifugal microfluidic system with a new fluid-assisted separation technique (FAST) and detected by cytomorphological evaluation using fluorescence microscopy. RESULTS: Two or more CTCs were detected using FAST in 74 patients and 3 healthy volunteers. The number of CTCs in the CRC group was significantly higher than that in the healthy volunteers (P < 0.001). When a receiver operating characteristic curve was created to differentiate patients with CRC from healthy volunteers, the sensitivity and specificity were almost optimized when the critical CTC value was 5/7.5 mL of blood. When this value was used, the sensitivity and specificity in differentiating patients with CRC from the healthy controls were 75% and 100%, respectively. In patients with CRC with ≥5 CTCs, vascular invasion was frequently identified (P = 0.035). All patients with stage IV were positive for CTCs. Patients with ≥5 CTCs showed a trend toward poor overall and progression-free survival. DISCUSSION: Our study demonstrated promising results with the use of FAST-based CTC detection for the early diagnosis and prognosis of CRC.

Circulating tumor cells detected by lab-on-a-disc: Role in early diagnosis of gastric cancer.

BACKGROUND: The use of circulating tumor cells (CTCs) as an early diagnostic biomarker and prognostic indicator after surgery or chemotherapy has been suggested for various cancers. This study aimed to evaluate CTCs in patients who underwent gastrectomy for gastric cancer and to explore their clinical usefulness in the early diagnosis of gastric cancer. METHODS: A total of 116 patients with gastric cancer who underwent gastrectomy and 31 healthy volunteers were prospectively included between 2014 and 2015. Peripheral blood samples were collected before gastrectomy, and CTCs were examined using a centrifugal microfluidic system with a new fluid-assisted separation technique. RESULTS: After creating a receiver operating characteristic curve to identify the discriminative CTC value needed differentiate patients with gastric cancer from healthy volunteers, sensitivity and specificity were nearly optimized at a CTC threshold of 2 per 7.5 mL of blood. Of the 102 persons with a CTC level ≥2 per 7.5 mL of blood, 99 (97.1%) had gastric cancer, and of the 45 persons with a CTC level <2 per 7.5 mL of blood, 28 (62.2%) were healthy controls. Accordingly, the sensitivity and specificity for the differentiation of patients with gastric cancer from healthy controls were 85.3% and 90.3%, respectively. However, the presence of CTCs was not associated with any clinicopathologic features such as staging, histologic type, or mucin phenotype. CONCLUSION: Although we could not prove the clinical feasibility of CTCs for gastric cancer staging, our results suggest a potential role of CTCs as an early diagnostic biomarker of gastric cancer.

[Measurement of telomerase activity and telomerase reverse transcriptase expression in gastric fluid and tissue for early diagnosis of stomach cancer].

BACKGROUND/AIMS: Telomerase activity and telomerase reverse transcriptase (TERT) expression have been proposed as a marker for malignancy. However, little is known about those markers in intestinal metaplasia (IM). This study was performed to evaluate the usefulness of telomerase activity in gastric washing fluid and TERT expression in tissue as a marker for early diagnosis of stomach cancer. METHODS: Gastric washing fluid and biopsies were taken endoscopically. We examined the telomerase activity by telomeric repeat amplification protocol (TRAP) and the TERT expression by semiquantitative reverse transcription-polymerase chain reaction in 26, 21 and 15 cases of cancer, IM, and normal mucosa respectively. RESULTS: The telomerase activity was positive in 65% of cancer, 44% of incomplete IM, and 33% of complete IM. The TERT was expressed in 89% of cancer, 81% of IM, but not in normal mucosa. The TERT expression level was higher in cancer and incomplete IM than in complete IM and normal mucosa (p<0.05). CONCLUSIONS: Telomerase activity in gastric washing fluid and TERT expression in tissue may have limited usefulness as a marker for the early diagnosis of stomach cancer. However, the increased levels of TERT expression in IM and cancer suggest that TERT expression may be associated with carcinogenesis in stomach cancer.

[Prophylactic effect of Lactobacillus GG in animal colitis and its effect on cytokine secretion and mucin gene expressions].

BACKGROUND/AIMS: Lactobacillus rhamnosus GG (LGG) has been used in acute colitis treatment. However, it is unclear whether the LGG prevents chronic colitis. The aim of this study was to examine the prophylactic effect of LGG on animal colitis, cytokine secretion, and mucin gene expression. METHODS: BALB/c mice (n=64) were exposed to 5% dextran sulfate sodium (DSS) for 7 days followed by 10 days recovery period and repeatedly exposed for 4 days. Then, the mice were devided into three group; group of oral LGG adminstration throughout the recovery and repeated colitis period; PBS group of PBS administration; control group. Colon length, histologic score, tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10) levels, mucin gene expressions were determined at each period. RESULTS: In acute colitis period, the LGG group showed higher levels of disease activity index (DAI), histologic score, TNF-alpha, IL-10, but shorter colon length, lower levels of mucin gene expressions than the control group. However, in repeated colitis period, the LGG group showed markedly lower levels of DAI and IL-10 but significantly longer colon length than PBS group (p<0.05). There was no difference in the mucin gene expression. CONCLUSIONS: These results suggest that LGG prevents chronic murine colitis. It may be associated with cytokine modulation and competitive inhibition of pathogenic bacteria. However, it may not be related with gene expression.

Relationship between symptom-onset-to-balloon time and long-term mortality in patients with acute myocardial infarction treated with drug-eluting stents.

BACKGROUND: Time from hospital arrival to reperfusion in ST-segment elevation myocardial infarction (STEMI) has been predictive of in-hospital mortality. The purpose of this study was to evaluate the relationship between symptom-onset-to-balloon time and long-term mortality in patients with STEMI in the drug-eluting stent (DES) era. METHODS: A series of 393 patients with STEMI treated with DES from 2005 to 2007 was stratified according to risk profile and preprocedural Thrombolysis In Myocardial Infarction (TIMI) flow grade, and clinical, angiographic, and follow-up data were collected. RESULTS: A total of 98 (24.9%) low-risk patients and 295 (75.1%) non-low-risk patients were identified. Three-year mortality rate was 3.1% for low-risk patients and 10.2% for non-low-risk patients (p=0.034), respectively; however it did not differ according to symptom-onset-to-balloon time in either low-risk (p=0.333) or non-low-risk patients (p=0.881). Similarly, symptom-onset-to-balloon time and mortality were not related to preprocedural TIMI flow (p=0.474 for TIMI 0-1; p=0.428 for TIMI 2-3). In multivariate analysis, final TIMI flow 0-2, systolic blood pressure <100 mmHg at admission, age ≥70 years, anterior infarction, C-reactive protein level, and peak creatine kinase myocardial band isoenzyme level were identified as independent predictors of 3-year mortality while symptom-onset-to-balloon time and preprocedural TIMI flow were not. CONCLUSIONS: In STEMI patients treated with DES, symptom-onset-to-balloon time does not affect long-term outcomes even in individuals at non-low risk and with poor preprocedural TIMI flow grade.

Clinical and angiographic outcomes of drug-eluting stents in patients with large vessel and single coronary artery lesion.

BACKGROUND: The aim of this study was to evaluate and compare the clinical and angiographic outcomes of 3 drug-eluting stents (DES) in patients with large vessel diameter and single coronary artery lesions. HYPOTHESIS: The efficacy of 3 DESs may be similar. METHODS: A total of 411 consecutive patients who visited 3 university hospitals from June 2004 to December 2007 and had a single coronary lesion which was treated with the use of a DES that was 3.5 mm in diameter were enrolled in this study. Patients were divided into 3 stent groups: Paclitaxel-eluting stent (PES, n = 105), Sirolimus-eluting stent (SES, n = 259), and Zotarolimus-eluting stent (ZES, n = 47). The study end point was a composite of major adverse cardiac events (MACE) including cardiac death, myocardial infarction (MI), and ischemia-driven target-vessel revascularization (TVR) for 12 months. RESULTS: Baseline characteristics were not different. Late loss was higher in the ZES group than the other stents (0.5 +/- 0.4 mm in SES vs 0.3 +/- 0.5 mm in PES, 0.7 +/- 0.5 mm in ZES, P = 0.001). The total MACE-free survival rate was not significantly different between the SES group and the PES group (98.8% in SES vs 97.1% in PES, P = 0.252) or the PES group and the ZES group (97.1% in PES vs 93.6% in ZES, P = 0.301). However, the SES group showed a significantly better MACE-free survival rate compared with the ZES group (98.8% in SES vs 93.6% in ZES, P = 0.018). CONCLUSIONS: Clinical and angiographic outcomes of DES in a large vessel diameter and single coronary artery is excellent and SES appears to show better angiographic and clinical outcomes than ZES.

Therapeutic strategy for in-stent restenosis based on the restenosis pattern after drug-eluting stent implantation.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the outcomes of repeated percutaneous coronary intervention (PCI) based on the restenosis pattern in drug-eluting stent (DES) failure. SUBJECTS AND METHODS: From April 2003 to March 2006, all 67 patients (67 lesions) at our 3 centers who had DES in-stent restenosis (ISR) were enrolled. The patients were divided into 3 groups: group I had focal edge restenosis, group II had focal body restenosis, and group III had non-focal restenosis. All patients were treated with conventional PCI including plain old balloon angioplasty (POBA), cutting balloon angioplasty (CBA), and repeated DES implantation (Re-DES). Angiographic and clinical one year follow-up results for the 3 groups were evaluated. RESULTS: Sixteen patients were enrolled in group I, 36 in group II, and 15 in group III. Baseline clinical and angiographic characteristics and the proportion of patients in each group receiving each type of treatment strategy were not significantly different among the groups. Within each group, a comparison of angiographic and clinical outcomes for each therapeutic modality revealed that restenosis rates were not statistically different. Although rates of major adverse cardiac events (MACE) were not statistically different between groups I and II, in group III, MACE were 3-fold higher for the POBA (4/4, 100.0%) and CBA (4/4, 100.0%) subgroups than for Re-DES (1/3, 33.3%) (p=0.06), but the differences did not reach statistical significance. CONCLUSION: THE PRESENT STUDY SUGGESTS THAT TREATMENT OF DES ISR SHOULD BE INDIVIDUALIZED ACCORDING TO RESTENOSIS PATTERN: any PCI strategy appears appropriate for focal ISR patterns, while Re-DES might be a better choice for non-focal ISR patterns.