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  • 1
    Online Resource
    Online Resource
    Tankyrase-selective inhibitor STP1002 shows preclinical antitumour efficacy without on-target toxicity in the gastrointestinal tract
    Elsevier BV ; 2022
    In:  European Journal of Cancer Vol. 173 ( 2022-09), p. 41-51
    Details
    In: European Journal of Cancer, Elsevier BV, Vol. 173 ( 2022-09), p. 41-51
    Type of Medium: Online Resource
    ISSN: 0959-8049
    URL: Article
    DOI: 10.1016/j.ejca.2022.06.031
    RVK:
    XA 42017.A
    RVK:
    XA 42017
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 1120460-6
    detail.hit.zdb_id: 1468190-0
    detail.hit.zdb_id: 82061-1
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  • 2
    Online Resource
    Online Resource
    Low-temperature Oxidation of Odor Compounds over La-based Perovskite Catalyst
    The Korean Institute of Chemical Engineers ; 2011
    In:  Korean Chemical Engineering Research Vol. 49, No. 2 ( 2011-04-30), p. 168-174
    Details
    In: Korean Chemical Engineering Research, The Korean Institute of Chemical Engineers, Vol. 49, No. 2 ( 2011-04-30), p. 168-174
    Type of Medium: Online Resource
    ISSN: 0304-128X
    Uniform Title: 란탄 기반 페롭스카이트 촉매를 이용한 악취 유발 물질의 저온 산화 반응
    URL: Article
    DOI: 10.9713/kcer.2011.49.2.168
    Language: English
    Publisher: The Korean Institute of Chemical Engineers
    Publication Date: 2011
    detail.hit.zdb_id: 2828582-7
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  • 3
    Online Resource
    Online Resource
    Abstract 491: Tankyrase-selective inhibitor STP1002 reverses resistance to MEK inhibitors in colorectal cancer with KRAS mutations
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 491-491
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 491-491
    Abstract: Mitogen-activated protein kinase (MEK) inhibitors have shown promising results in KRAS-mutated cancers with constitutive activation of the RAS/RAF/MEK pathway. However, the intrinsic and acquired resistance to MEK inhibitors is frequently observed in clinical trials. Wnt/β-catenin signaling hyper-activation is reported to be responsible for such resistance in colorectal cancer (CRC). Herein, we introduce a novel tankyrase inhibitor STP1002 to revert the intrinsic and acquired resistance to MEK inhibitors in KRAS-mutated CRC. Dual combination of STP1002 and MEK inhibitor synergistically reduced the oncogenic activity of KRAS (G12V or G12D)-mutated CRC cell lines. Data also showed that concomitant treatment with STP1002 and MEK inhibitor dramatically inhibited tumor growth of KRAS (G12V)-mutated CRC xenograft animal models. Moreover, the combination treatment sensitized the acquired MEK inhibitor-resistant CRC cells and suppressed the Wnt/YAP pathway which is the bypass mechanism of MEK inhibitor resistance. Dual combination of STP1002 and MEK inhibitor is a promising candidate to overcome resistance to MEK inhibitors in colorectal cancer with KRAS-G12V/G12D mutations. The phase 1 clinical trial study is ongoing in order to show safety margin. Citation Format: Young-Ju Kwon, Dong Young Kim, Uk-Il Kim, Xue Meng, Ho Kyun Lee, Hyung Tae Bang, Jae-Sung Kim, Kyungjin Kim. Tankyrase-selective inhibitor STP1002 reverses resistance to MEK inhibitors in colorectal cancer with KRAS mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 491.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-491
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Tankyrase-Selective Inhibitor Stp1002 Shows Preclinical Antitumor Efficacy Without On-Target Toxicity in the Gastrointestinal Tract
    Elsevier BV ; 2022
    In:  SSRN Electronic Journal
    Details
    In: SSRN Electronic Journal, Elsevier BV
    Type of Medium: Online Resource
    ISSN: 1556-5068
    URL: Article
    DOI: 10.2139/ssrn.4065567
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 5
    Online Resource
    Online Resource
    Abstract 5171: Design and development of a tankyrase inhibitor STP06-1002 as an anticancer therapeutic agent
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5171-5171
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5171-5171
    Abstract: Background The Wnt/β-catenin signaling pathway plays a pivotal role in numerous biological processes and its dysregulation has been implicated in diverse oncolytic initiation. Aberrant overactivation of the Wnt/β-catenin pathway due to overexpression and accumulation of the β-catenin has been often observed in colorectal cancer (CRC). As a member of PARP family (PARP5 isoform), tankyrase (TNKS) regulates stability of the β-catenin destruction complex through Axin poly-ADP ribosylation maintaining homeostasis of level of the β-catenin. Axin is a rate-limiting component of the destruction complex and inhibition of tankyrase stabilizes Axin level to prevent subsequently CRC development by downregulation of the Wnt target genes. We herein report an orally-active tankyrase inhibitor STP06-1002 with excellent cellular potency, good ADME properties, and in vivo anti-tumor efficacy with moderate safety. Results The novel tankyrase inhibitor STP06-1002 shows good inhibition activities with IC50 29.9 nM (TNKS1) and 3.7 nM (TNKS2) and its excellent cellular potency with IC50 6.7 nM (TCF/LEF). STP06-1002 also shows excellent selectivity against PARP1 isoform with IC50 & gt;10 μM. STP06-1002 has good ADME properties, particularly low CYP450 inhibition & induction in CYP3A and PXR, suggesting no DDI issues. It also displays good in vivo pharmacokinetic profiles in rats (B.A. [F] & gt;60%) and dogs (27%). No significant toxicity issues are observed from cytotoxicity studies, hERG assay and Ames test. The off-target studies in both Pan Kinase panel (against 75 cancer-focused kinases) and Lead Profiling Screen® (against 68 receptors and ion channels) prove its high selectivity. In the xenograft efficacy studies for in vivo proof-of-concept, the dose-dependent effect on Colo320DM (Wnt-dependent, KRas wild type) shows tumor growth inhibition with 45% and DLD-1 (Wnt-dependent, KRas mutant) with 60%. In the case of Wnt-independent cell lines HCT116 and RKO as negative controls, both did not show any tumor growth inhibition effects. Dose range finding study of rodent (rat) resulted in maximum tolerated dose of (MTD) 200 mg/kg/day, and the corresponding of non-rodent (dog) MTD of 30 mg/kg/day. Taking these promising preclinical results of optimal in vivo efficacy dose, MTD and HSTD (50 mg/kg/day) into account, we suggest safety margin of the STP06-1002 as 6 to 11 folds applicable to clinical human dosages. Discussion The preclinical studies of STP06-1002 show successfully its potentials as an anticancer therapeutic agent. Based on the excellent biological and preclinical profiles, STP06-1002 will be a suitable candidate as an orally-active novel TNKS inhibitor and move toward phase I clinical trials with strong biomarker-based strategies. Citation Format: Kyungjin Kim, Uk-Il Kim, Hyung Tae Bang, Jihye Yoon, Jin Ha Hwang, Jung-Nyoung Heo, Kwang-Rok Kim, Hwan Jung Lim, Jai-Hee Moon, Eun Young Lee, Seul Lee, Dong-Hoon Jin. Design and development of a tankyrase inhibitor STP06-1002 as an anticancer therapeutic agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5171. doi:10.1158/1538-7445.AM2017-5171
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5171
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
    Online Resource
    Online Resource
    Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer : 5-Year Outcomes of the KLASS-02 Randomized Clinical Trial
    American Medical Association (AMA) ; 2022
    In:  JAMA Surgery Vol. 157, No. 10 ( 2022-10-01), p. 879-
    Details
    In: JAMA Surgery, American Medical Association (AMA), Vol. 157, No. 10 ( 2022-10-01), p. 879-
    Abstract: The long-term safety of laparoscopic distal gastrectomy for locally advanced gastric cancer (AGC) remains uncertain given the lack of 5-year follow-up results. Objective To compare the 5-year follow-up results in patients with clinically AGC enrolled in the Korean Laparoendoscopic Gastrointestinal Surgery Study (KLASS)-02 randomized clinical trial who underwent laparoscopic or open distal gastrectomy. Design, Setting, and Participants The KLASS-02, a multicenter randomized clinical trial, showed that laparoscopic surgery was noninferior to open surgery for patients with locally AGC. The present study assessed the 5-year follow-up results, including 5-year overall survival (OS) and relapse-free survival (RFS) rates and long-term complications, in patients enrolled in KLASS-02. From November 21, 2011, to April 29, 2015, patients aged 20 to 80 years diagnosed preoperatively with locally AGC were enrolled. Final follow-up was on June 15, 2021. Data were analyzed June 24 to September 9, 2021. Interventions Patients were treated with R0 resection either by laparoscopic gastrectomy or open gastrectomy as the full analysis set of the KLASS-02 trial. Main Outcomes and Measures Five-year OS and RFS rates, recurrence patterns, and long-term surgical complications were evaluated. Results This study enrolled a total of 1050 patients. A total of 974 patients were treated with R0 resection; 492 (50.5%) in the laparoscopic gastrectomy group (mean [SD] age, 59.8 [11.0] years; 351 men [71.3%]) and 482 (49.5%) in the open gastrectomy group (mean [SD] age, 59.4 [11.5] years; 335 men [69.5%] ). In patients who underwent laparoscopic and open distal gastrectomy, the 5-year OS (88.9% vs 88.7%) and RFS (79.5% vs 81.1%) rates did not differ significantly. The most common types of recurrence were peritoneal carcinomatosis (73 of 173 [42.1%]), hematogenous metastases (36 of 173 [20.8%] ), and locoregional recurrence (23 of 173 [13.2%]), with no between-group differences in types of recurrence at each cancer stage. The correlation between 3-year RFS and 5-year OS at the individual level was highest in patients with stage III gastric cancer (ρ = 0.720). The late complication rate was significantly lower in the laparoscopic than in the open surgery group (32 of 492 [6.5%] vs 53 of 482 [11.0%]). The most common type of complication in both groups was intestinal obstruction (13 of 492 [2.6%] vs 24 of 482 [5.0%]). Conclusions and Relevance The 5-year outcomes of the KLASS-02 trial support the 3-year results, which is the noninferiority of laparoscopic surgery compared with open gastrectomy for locally AGC. The laparoscopic approach can be recommended in patients with locally AGC to achieve the benefit of low incidence of late complications. Trial Registration ClinicalTrials.gov Identifier: NCT01456598
    Type of Medium: Online Resource
    ISSN: 2168-6254
    URL: Article
    DOI: 10.1001/jamasurg.2022.2749
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
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  • 7
    Online Resource
    Online Resource
    Intensive vs Conventional Blood Pressure Lowering After Endovascular Thrombectomy in Acute Ischemic Stroke : The OPTIMAL-BP Randomized Clinical Trial
    American Medical Association (AMA) ; 2023
    In:  JAMA Vol. 330, No. 9 ( 2023-09-05), p. 832-
    Details
    In: JAMA, American Medical Association (AMA), Vol. 330, No. 9 ( 2023-09-05), p. 832-
    Abstract: Optimal blood pressure (BP) control after successful reperfusion with endovascular thrombectomy (EVT) for patients with acute ischemic stroke is unclear. Objective To determine whether intensive BP management during the first 24 hours after successful reperfusion leads to better clinical outcomes than conventional BP management in patients who underwent EVT. Design, Setting, and Participants Multicenter, randomized, open-label trial with a blinded end-point evaluation, conducted across 19 stroke centers in South Korea from June 2020 to November 2022 (final follow-up, March 8, 2023). It included 306 patients with large vessel occlusion acute ischemic stroke treated with EVT and with a modified Thrombolysis in Cerebral Infarction score of 2b or greater (partial or complete reperfusion). Interventions Participants were randomly assigned to receive intensive BP management (systolic BP target & amp;lt;140 mm Hg; n = 155) or conventional management (systolic BP target 140-180 mm Hg; n = 150) for 24 hours after enrollment. Main Outcomes and Measures The primary outcome was functional independence at 3 months (modified Rankin Scale score of 0-2). The primary safety outcomes were symptomatic intracerebral hemorrhage within 36 hours and death related to the index stroke within 3 months. Results The trial was terminated early based on the recommendation of the data and safety monitoring board, which noted safety concerns. Among 306 randomized patients, 305 were confirmed eligible and 302 (99.0%) completed the trial (mean age, 73.0 years; 122 women [40.4%]). The intensive management group had a lower proportion achieving functional independence (39.4%) than the conventional management group (54.4%), with a significant risk difference (−15.1% [95% CI, −26.2% to −3.9%] ) and adjusted odds ratio (0.56 [95% CI, 0.33-0.96]; P  = .03). Rates of symptomatic intracerebral hemorrhage were 9.0% in the intensive group and 8.1% in the conventional group (risk difference, 1.0% [95% CI, −5.3% to 7.3%]; adjusted odds ratio, 1.10 [95% CI, 0.48-2.53] ; P  = .82). Death related to the index stroke within 3 months occurred in 7.7% of the intensive group and 5.4% of the conventional group (risk difference, 2.3% [95% CI, −3.3% to 7.9%]; adjusted odds ratio, 1.73 [95% CI, 0.61-4.92] ; P  = .31). Conclusions and Relevance Among patients who achieved successful reperfusion with EVT for acute ischemic stroke with large vessel occlusion, intensive BP management for 24 hours led to a lower likelihood of functional independence at 3 months compared with conventional BP management. These results suggest that intensive BP management should be avoided after successful EVT in acute ischemic stroke. Trial Registration ClinicalTrials.gov Identifier: NCT04205305
    Type of Medium: Online Resource
    ISSN: 0098-7484
    URL: Article
    DOI: 10.1001/jama.2023.14590
    RVK:
    XA 10000
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
    detail.hit.zdb_id: 2958-0
    detail.hit.zdb_id: 2018410-4
    SSG: 5,21
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  • 8
    Online Resource
    Online Resource
    Comparison of the Oral Calcimimetics Evocalcet and Cinacalcet in East Asian Patients on Hemodialysis with Secondary Hyperparathyroidism
    Elsevier BV ; 2023
    In:  Kidney International Reports ( 2023-8)
    Details
    In: Kidney International Reports, Elsevier BV, ( 2023-8)
    Type of Medium: Online Resource
    ISSN: 2468-0249
    URL: Article
    DOI: 10.1016/j.ekir.2023.08.034
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2887223-X
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  • 9
    Online Resource
    Online Resource
    Benefit of Targeting a LDL (Low-Density Lipoprotein) Cholesterol 〈70 mg/dL During 5 Years After Ischemic Stroke
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Stroke Vol. 51, No. 4 ( 2020-04), p. 1231-1239
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. 4 ( 2020-04), p. 1231-1239
    Abstract: The TST trial (Treat Stroke to Target) evaluated the benefit of targeting a LDL (low-density lipoprotein) cholesterol of 〈 70 mg/dL to reduce the risk of cardiovascular events in 2860 patients with ischemic stroke with atherosclerotic stenosis of cerebral vasculature or aortic arch plaque 〉 4 mm, in a French and Korean population. The follow-up lasted a median of 5.3 years in French patients (similar to the median follow-up time in the SPARCL trial [Stroke Prevention by Aggressive Reduction in Cholesterol Level]) and 2.0 years in Korean patients. Exposure duration to statin is a well-known driver for cardiovascular risk reduction. We report here the TST results in the French cohort. Methods— One thousand seventy-three French patients were assigned to 〈 70 mg/dL (1.8 mmol/L) and 1075 to 100±10 mg/dL (90–110 mg/dL, 2.3–2.8 mmol/L). To achieve these goals, investigators used the statin and dosage of their choice and added ezetimibe on top if needed. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization and vascular death. Results— After a median follow-up of 5.3 years, the achieved LDL cholesterol was 66 (1.69 mmol/L) and 96 mg/dL (2.46 mmol/L) on average, respectively. The primary end point occurred in 9.6% and 12.9% of patients, respectively (HR, 0.74 [95% CI, 0.57–0.94]; P =0.019). Cerebral infarction or urgent carotid revascularization following transient ischemic attack was reduced by 27% ( P =0.046). Cerebral infarction or intracranial hemorrhage was reduced by 28% ( P =0.023). The primary outcome or intracranial hemorrhage was reduced by 25% ( P =0.021). Intracranial hemorrhages occurred in 13 and 11 patients, respectively (HR, 1.17 [95% CI, 0.53–2.62]; P =0.70). Conclusions— After an ischemic stroke of documented atherosclerotic origin, targeting a LDL cholesterol of 〈 70 mg/dL during 5.3 years avoided 1 subsequent major vascular event in 4 (number needed to treat of 30) and no increase in intracranial hemorrhage. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01252875.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.119.028718
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1467823-8
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  • 10
    Online Resource
    Online Resource
    Intracranial Hemorrhage in the TST Trial
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Stroke Vol. 53, No. 2 ( 2022-02), p. 457-462
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 53, No. 2 ( 2022-02), p. 457-462
    Abstract: Although statins are effective in secondary prevention of ischemic stroke, they are also associated with an increase risk of intracranial hemorrhage (ICH) in certain conditions. In the TST trial (Treat Stroke to Target), we prespecified an exploration of the predictors of incident ICH. Methods: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned in a 1:1 ratio to a target LDL (low-density lipoprotein) cholesterol of 〈 70 mg/dL or 100±10 mg/dL, using statin or ezetimibe. Results: Among 2860 patients enrolled, 31 incident ICH occurred over a median follow-up of 3 years (18 and 13 in the lower and higher target group, 3.21/1000 patient-years [95% CI, 2.38–4.04] and 2.32/1000 patient-years [95% CI, 1.61–3.03] , respectively). While there were no baseline predictors of ICH, uncontrolled hypertension (HR, 2.51 [95% CI, 1.01–6.31], P =0.041) and being on anticoagulant (HR, 2.36 [95% CI, 1.00–5.62], P =0.047)] during the trial were significant predictors. On-treatment low LDL cholesterol was not a predictor of ICH. Conclusions: Targeting an LDL cholesterol of 〈 70 mg/dL compared with 100±10 mg/dL in patients with atherosclerotic ischemic stroke nonsignificantly increased the risk of ICH. Incident ICHs were not associated with low LDL cholesterol. Uncontrolled hypertension and anticoagulant therapy were associated with ICH which has important clinical implications. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01252875; EUDRACT identifier: 2009-A01280-57.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.121.035846
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467823-8
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