Publications by authors named "Yu Takahashi"

343 Publications

Peptide-to-Small Molecule: A Pharmacophore-Guided Small Molecule Lead Generation Strategy from High-Affinity Macrocyclic Peptides.

J Med Chem 2022 Aug 29;65(15):10655-10673. Epub 2022 Jul 29.

Pharmaceutical Research Division, Shionogi Pharmaceutical Research Center, 3-1-1 Futaba-cho, Toyonaka, Osaka561-0825, Japan.

Recent technological innovations have led to the development of methods for the rapid identification of high-affinity macrocyclic peptides for a wide range of targets; however, it is still challenging to achieve the desired activity and membrane permeability at the same time. Here, we propose a novel small molecule lead discovery strategy, ″Peptide-to-Small Molecule″, which is a combination of rapid identification of high-affinity macrocyclic peptides peptide display screening followed by pharmacophore-guided design of small molecules, and demonstrate the applicability using nicotinamide -methyltransferase (NNMT) as a target. Affinity selection by peptide display technology identified macrocyclic peptide that exhibited good enzymatic inhibitory activity but no cell-based activity. Thereafter, a peptide pharmacophore-guided design and further structure-based optimization resulted in highly potent and cell-active small molecule (cell-free IC = 0.0011 μM, cell-based IC = 0.40 μM), indicating that this strategy could be a new option for drug discovery.
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http://dx.doi.org/10.1021/acs.jmedchem.2c00919DOI Listing
August 2022

Endoscopic Treatment of Superficial Gastric Cancer: Present Status and Future.

Curr Oncol 2022 Jul 4;29(7):4678-4688. Epub 2022 Jul 4.

Department of Gastroenterology, The University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Although the mortality rates of gastric cancer (GC) are gradually declining, gastric cancer is still the fourth leading cause of cancer-related death worldwide. This may be due to the high rate of patients who are diagnosed with GC at advanced stages. However, in countries such as Japan with endoscopic screening systems, more than half of GCs are discovered at an early stage, enabling endoscopic resection (ER). Especially after the introduction of endoscopic submucosal dissection (ESD) in Japan around 2000, a high en bloc resection rate allowing pathological assessment of margin and depth has become possible. While ER is a diagnostic method of treatment and may not always be curative, it is widely accepted as standard treatment because it is less invasive than surgery and can provide an accurate diagnosis for deciding whether additional surgery is necessary. The curability of ER is currently assessed by the completeness of primary tumor removal and the possibility of lymph node metastasis. This review introduces methods, indications, and curability criteria for ER of EGC. Despite recent advances, several problems remain unsolved. This review will also outline the latest evidence concerning future issues.
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http://dx.doi.org/10.3390/curroncol29070371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9319225PMC
July 2022

Successful endovascular treatment of a ruptured bihemispheric posterior inferior cerebellar artery aneurysm: illustrative case.

J Neurosurg Case Lessons 2021 Aug 16;2(7):CASE21367. Epub 2021 Aug 16.

Department of Neurological Surgery, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa, Japan.

Background: Normal posterior inferior cerebellar artery (PICA) anatomy is highly variable, but bihemispheric PICA crossing the midline to supply the vascular territory of bilateral cerebellar hemisphere is rare. Herein, the authors reported a rare case of ruptured aneurysm that was associated with bihemispheric PICA and successfully treated endovascularly.

Observations: A 46-year-old woman presented with sudden headache and loss of consciousness because of an intraventricular hemorrhage due to a ruptured aneurysm that was associated with the bihemispheric PICA. Angiography revealed that the aneurysm was located at the bifurcation between the bihemispheric PICA and the bilateral distal PICA. The ruptured aneurysm was successfully occluded using coil embolization, which preserved the parent artery with no procedural-related complication.

Lessons: To the best of the authors' knowledge, this was the first report of a ruptured aneurysm associated with bihemispheric PICA being successfully treated endovascularly. Aneurysm formation may be accelerated by hemodynamic stress and vascular fragility. For neurosurgeons and neurointerventionalists, it is important to understand the anatomical variation of PICA, especially bihemispheric PICA, which is a potential risk factor for a fatal stroke.
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http://dx.doi.org/10.3171/CASE21367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9265170PMC
August 2021

Clinical Validation of a Virtual Planner for Coronary Interventions Based on Coronary CT Angiography.

JACC Cardiovasc Imaging 2022 07 13;15(7):1242-1255. Epub 2022 Apr 13.

Cardiovascular Center Aalst, OLV Clinic, Aalst, Belgium. Electronic address:

Background: Low fractional flow reserve (FFR) values after percutaneous coronary intervention (PCI) carry a worse prognosis than high post-PCI FFR values. Therefore, the ability to predict post-PCI FFR might play an important role in procedural planning. Post-PCI FFR values can now be computed from pre-PCI coronary computed tomography angiography (CTA) using the fractional flow reserve derived from coronary computed tomography angiography revascularization planner (FFR Planner).

Objectives: The aim of this study was to validate the accuracy of the FFR Planner.

Methods: In this multicenter, investigator-initiated, prospective study, patients with chronic coronary syndromes and significant lesions based on invasive FFR ≤0.80 were recruited. The FFR Planner was applied to the fractional flow reserve derived from coronary computed tomography angiography (FFR) model, simulating PCI. The primary objective was the agreement between the predicted post-PCI FFR by the FFR Planner and measured post-PCI FFR. Accuracy of the FFR Planner's luminal dimensions was assessed by using post-PCI optical coherence tomography as the reference.

Results: Overall, 259 patients were screened, with 120 patients (123 vessels) included in the final analysis. The mean patient age was 64 ± 9 years, and 24% had diabetes. Measured FFR post-PCI was 0.88 ± 0.06, and the FFR Planner FFR was 0.86 ± 0.06 (mean difference: 0.02 ± 0.07 FFR unit; limits of agreement: -0.12 to 0.15). Optical coherence tomography minimal stent area was 5.60 ± 2.01 mm, and FFR Planner minimal stent area was 5.0 ± 2.2 mm (mean difference: 0.66 ± 1.21 mm; limits of agreement: -1.7 to 3.0). The accuracy and precision of the FFR Planner remained high in cases with focal and diffuse disease and with low and high calcium burden.

Conclusions: The FFR-based technology was accurate and precise for predicting FFR after PCI. (Precise Percutaneous Coronary Intervention Plan Study [P3]; NCT03782688).
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http://dx.doi.org/10.1016/j.jcmg.2022.02.003DOI Listing
July 2022

Percutaneous transhepatic obliteration for rupture of varices in the small intestine: a case report.

Clin J Gastroenterol 2022 Jul 1. Epub 2022 Jul 1.

Third Department of Internal Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.

Rupture of ectopic varices is a rare but serious complication of portal hypertension. A 65-year-old woman with liver cirrhosis caused by primary biliary cholangitis visited the emergency department with several episodes of melena. Computed tomography revealed varices in the small intestine. We successfully performed percutaneous transhepatic obliteration using coil embolization. The patient had no episodes of re-bleeding after treatment. Percutaneous transhepatic obliteration may be a useful option for the treatment of varices in the small intestine.
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http://dx.doi.org/10.1007/s12328-022-01660-2DOI Listing
July 2022

Reproduction of modified Blumgart pancreaticojejunostomy in a robotic environment: a simple clipless technique.

Surg Endosc 2022 Jun 30. Epub 2022 Jun 30.

Division of Hepato-Biliary-Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Background: Although modified Blumgart anastomosis (MBA) in robotic pancreaticoduodenectomy has been accepted as a simple and safe procedure that provides non-inferior surgical outcomes compared to open MBA, the details of the standardization of robotic MBAs have never been established. In this report, we detail the technical tips to reproduce MBA in the robotic environment.

Materials And Methods: From January to December in 2021, 16 patients underwent our novel robotic MBA technique, which included clipless Blumgart suture and duct-to-mucosa anastomosis. To simplify the manipulation of sutures in robotic environment, short double-armed sutures in 15 cm length were created and used for Blumgart suture. Duct-to-mucosa anastomosis were done by 5-0 monofilament of 6 cm length. These tips enabled clipless anastomosis and minimized the burden of the patient-side assistant. Surgical and short-term outcomes were compared between patients with robotic MBA (Robo group) and those who underwent open MBA during 2021 (32 patients, Open group).

Results: The median operation time was significantly longer in the Robo group than in the Open group (551 vs. 485.5 min, P = 0.0027). Estimated blood loss was significantly lower in the Robo group than in the open group (95 vs. 355 mL, P < 0.0002). The median duration of clipless MBA in the Robo group was 56 (46-68) min. The incidence of POPF (grade B or C) was not significantly different among the groups (19% vs. 22%, P = 0.71). The mean length of hospital stay was significantly shorter in the Robo group than in the Open group (18 vs. 24 days, P = 0.019).

Conclusion: Clipless MBA in a robotic environment was safely performed with acceptable short-term outcomes and can be proposed as a standard technique for robotic pancreatojejunostomy.
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http://dx.doi.org/10.1007/s00464-022-09397-2DOI Listing
June 2022

Gel Immersion Endoscopic Mucosal Resection (EMR) for Superficial Nonampullary Duodenal Epithelial Tumors May Reduce Procedure Time Compared with Underwater EMR (with Video).

Gastroenterol Res Pract 2022 15;2022:2040792. Epub 2022 Jun 15.

The Third Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan.

Materials And Methods: This was a retrospective cohort study conducted in two municipal hospitals. We identified 24 patients with SNADETs of 3-18 mm in diameter who underwent UEMR or GIEMR. One lesion was excluded from the analysis because it was found to be in the stomach after surgery. The primary outcome was procedure time.

Results: GIEMR significantly reduced the procedure time compared with UEMR (5 min vs. 10 min, = 0.016). There was no significant difference between the UEMR and GIEMR groups for resection rate (93% vs. 100%, = 1.0) and R0 resection rate (57% vs. 80%, = 0.39). No serious complications were observed in either group.

Conclusions: GIEMR of SNADET has the potential to reduce procedure time compared with UEMR and may be particularly effective in areas where immersion in water is difficult.
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http://dx.doi.org/10.1155/2022/2040792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9217606PMC
June 2022

Organoid-derived intestinal epithelial cells are a suitable model for preclinical toxicology and pharmacokinetic studies.

iScience 2022 Jul 7;25(7):104542. Epub 2022 Jun 7.

Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.

Intestinal organoids are physiologically relevant tools used for cellular models. However, the suitability of organoids to examine biological functions over existing established cell lines lacks sufficient evidence. Cytochrome P450 3A4 (CYP3A4) induction by pregnane X receptor ligands, glucose uptake via sodium/glucose cotransporter 1, and microsomal triglyceride transfer protein-dependent ApoB-48 secretion, which are critical for human intestinal metabolism, were observed in organoid-derived two-dimensional cells but little in Caco-2 cells. CYP3A4 induction evaluation involved a simplified method of establishing organoids that constitutively expressed a reporter gene. Compound screening identified several anticancer drugs with selective activities toward Caco-2 cells, highlighting their characteristics as cancer cells. Another compound screening revealed a decline in N-(4-hydroxyphenyl)retinamide cytotoxicity upon rifampicin treatment in organoid-derived cells, under CYP3A4-induced conditions. This study shows that organoid-derived intestinal epithelial cells (IECs) possess similar physiological properties as intestinal epithelium and can serve as tools for enhancing the prediction of biological activity in humans.
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http://dx.doi.org/10.1016/j.isci.2022.104542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9218437PMC
July 2022

Depolarization time and extracellular glutamate levels aggravate ultraearly brain injury after subarachnoid hemorrhage.

Sci Rep 2022 Jun 17;12(1):10256. Epub 2022 Jun 17.

Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Early brain injury after aneurysmal subarachnoid hemorrhage (SAH) worsens the neurological outcome. We hypothesize that a longer duration of depolarization and excessive release of glutamate aggravate neurological outcomes after SAH, and that brain hypothermia can accelerate repolarization and inhibit the excessive release of extracellular glutamate and subsequent neuronal damage. So, we investigated the influence of depolarization time and extracellular glutamate levels on the neurological outcome in the ultra-early phase of SAH using a rat injection model as Experiment 1 and then evaluated the efficacy of brain hypothermia targeting ultra-early brain injury as Experiment 2. Dynamic changes in membrane potentials, intracranial pressure, cerebral perfusion pressure, cerebral blood flow, and extracellular glutamate levels were observed within 30 min after SAH. A prolonged duration of depolarization correlated with peak extracellular glutamate levels, and these two factors worsened the neuronal injury. Under brain hypothermia using pharyngeal cooling after SAH, cerebral perfusion pressure in the hypothermia group recovered earlier than that in the normothermia group. Extracellular glutamate levels in the hypothermia group were significantly lower than those in the normothermia group. The early induction of brain hypothermia could facilitate faster recovery of cerebral perfusion pressure, repolarization, and the inhibition of excessive glutamate release, which would prevent ultra-early brain injury following SAH.
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http://dx.doi.org/10.1038/s41598-022-14360-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205962PMC
June 2022

Trends in proton pump inhibitor use, reflux esophagitis, and various upper gastrointestinal symptoms from 2010 to 2019 in Japan.

PLoS One 2022 17;17(6):e0270252. Epub 2022 Jun 17.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

The increasing usage of proton pump inhibitors (PPIs) has been reported worldwide, but information on PPI use in East Asia is inadequate. This study aimed to examine the trends in PPI use in Japan, along with the changes in histamine H2 receptor antagonist (H2RA) use, disease rate of reflux esophagitis, and the prevalence of upper gastrointestinal symptoms. We analyzed 217,712 healthy subjects (127,607 men and 90,105 women; 51.4 ± 9.7 years old) participating in the health check program from 2010 to 2019. Various upper gastrointestinal symptoms were evaluated using the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) questionnaire. Reflux esophagitis was diagnosed by esophageal erosion using the Los Angeles classification grades A, B, C, and D. From 2010 to 2019, the percentage of PPI users increased markedly from approximately 1.8% to 5.3%, whereas that of H2RA users decreased gradually from approximately 2.5% to 1.9%. The use of all classical types of PPIs (omeprazole, lansoprazole, rabeprazole, and esomerazole) and a new type of PPI, a potassium-competitive acid blocker (vonoprazan), greatly increased during the 10 years. An upward trend in the prevalence of reflux esophagitis was observed from 2010 to 2015, but not from 2016 to 2019, indicating that the monotonic rising prevalence of reflux disease stopped in the middle of the 2010s in Japan. In contrast, various upper gastrointestinal symptoms significantly improved between 2010 and 2019. All 12 FSSG symptoms of PPI users were significantly worse than those of non-PPI users, suggesting that PPIs still cannot completely control upper gastrointestinal symptoms. In conclusion, this study revealed a significant increase in PPI use and a slight decrease in H2RA use from 2010 to 2019. Despite a plateau in the prevalence of reflux esophagitis and considerable improvement in various upper gastrointestinal symptoms, PPI use has continued to increase in Japan.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0270252PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205527PMC
June 2022

Repeat Resection for Advanced Colorectal Liver Metastases-Does it have the Potential for Cure?

World J Surg 2022 Sep 12;46(9):2253-2261. Epub 2022 Jun 12.

Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan.

Background: Although surgical resection is the only potential treatment for patients with colorectal liver metastases (CLM), the actual cure is rare in patients with advanced CLM. Repeat resection (RR) is the most effective treatment in patients with recurrence; however, whether patients with initially advanced CLM achieve cure throughout RR or experience repeated recurrence even after RR remains unclear. In this study, we analyzed whether patients with advanced CLM achieve cure after RR.

Methods: Consecutive patients who underwent initial hepatectomy with curative intent for CLM from January 1999 to August 2007 were included. Patients who were alive at 10 years from the initial hepatectomy without any evidence of recurrence were defined as cured. Cure rates were compared between patients with Fong's clinical risk score (CRS) of ≥ 3 and those with CRS of ≤ 2.

Results: A total of 257 patients were included and followed up. Among them, 93 (36.2%) patients achieved actual cure postoperatively. The cure rate of patients with a CRS of ≥ 3 was 32.4% (33/102), which was not different from that of patients with a CRS of ≤ 2 (38.7% [60/155]; p = 0.299), although former patients had higher recurrence rate after the initial hepatectomy than latter ones (85.3% vs. 72.3%; p = 0.014). The cure rates after the initial, second, and third resections were 23.0% (59/257), 30.0% (24/80), and 22.5% (7/31), respectively. In multivariate analysis, RR was determined as an independent favorable factor of achieving cure.

Conclusions: RR had a potential to cure patients with advanced CLM, and one-third of them achieved cure.
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http://dx.doi.org/10.1007/s00268-022-06616-8DOI Listing
September 2022

Effect of simultaneous testing of two mice in the tail suspension test and forced swim test.

Sci Rep 2022 06 2;12(1):9224. Epub 2022 Jun 2.

Department of Psychiatry, Kawasaki Medical School, Kurashiki, 701-0192, Japan.

In mouse studies, the results of behavioural experiments are greatly affected by differences in the experimental environment and handling methods. The Porsolt forced swim test and tail suspension test are widely used to evaluate predictive models of depression-like behaviour in mice. It has not been clarified how the results of these tests are affected by testing single or multiple mice simultaneously. Therefore, this study evaluated the differences between testing two mice simultaneously or separately. To investigate the effect of testing multiple mice simultaneously, the Porsolt forced swim test and tail suspension test were performed in three patterns: (1) testing with an opaque partition between two mice, (2) testing without a partition between two mice, and (3) testing a single mouse. In the Porsolt forced swim test, the mice tested simultaneously without a partition demonstrated increased immobility time as compared to mice tested alone. No difference in immobility time was observed between the three groups in the tail suspension test. Our results showed that the environment of behavioural experiments investigating depression-like behaviour in mice can cause a difference in depression-like behaviour. The results of this experiment indicated that it is necessary to describe the method used for behavioural testing in detail.
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http://dx.doi.org/10.1038/s41598-022-12986-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9163059PMC
June 2022

Real-world clinical outcomes of percutaneous transluminal septal myocardial ablation for patients with drug-refractory hypertrophic obstructive cardiomyopathy: results from a retrospective multicenter registry of non-high-volume centers.

Heart Vessels 2022 May 31. Epub 2022 May 31.

Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

Percutaneous transluminal septal myocardial ablation (PTSMA) is a well-established interventional therapy for drug-refractory hypertrophic obstructive cardiomyopathy (HOCM) as an alternative to surgical myectomy. Although guidelines recommend that PTSMA should be performed in institutions with extensive experience, it is not centralized to such high-volume centers in real-world clinical practice. Thus, this study aimed to assess the feasibility of PTSMA in non-high-volume centers. We retrospectively examined patients with HOCM who underwent PTSMA between August 2012 and May 2020 at four institutions that experienced fewer than 20 cases of PTSMA procedures. The primary clinical endpoint was a composite of safety (all-cause death, electrical defibrillation for ventricular tachycardia or fibrillation, cardiac tamponade, permanent pacemaker implantation, and repeated interventions) and efficacy endpoints (repeated interventions [PTSMA or surgical myectomy]). Fifty-eight consecutive patients were enrolled. During the 30-day follow-up, no major clinical adverse events were noted except three patients (5.2%) requiring permanent pacemaker implantation for complete atrioventricular block. The percentage of patients with New York Heart Association functional class 1 or 2 significantly increased from 8.6 to 100% (p < 0.001). In the Cox proportional hazard model, left ventricular outflow tract pressure gradient at rest ≥ 30 mmHg (hazard ratio [HR] 6.56; 95% confidence interval [CI] 1.44-29.90; p = 0.015) and mitral regurgitation grade ≥ 3 (HR 10.75; 95% CI 1.81-63.79; p = 0.009) at the 30-day follow-up were associated with a composite of major clinical adverse events. The current study demonstrated that 58 patients who underwent PTSMA in non-high-volume centers had favorable 30-day clinical outcomes, with a primary composite endpoint rate of 5.2%. A prospective study with a larger sample size and longer follow-up is warranted to verify the safety and efficacy of PTSMA in non-high-volume centers.
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http://dx.doi.org/10.1007/s00380-022-02100-4DOI Listing
May 2022

Segmental resection with partial mesopancreatic and mesojejunal excision (pMME) for duodenal carcinoma of the third or fourth portion.

Langenbecks Arch Surg 2022 May 30. Epub 2022 May 30.

Department of Hepatobiliary-Pancreatic Surgery, Juntendo University Graduate School of Medicine, Hongo, Tokyo, Japan.

Introduction: Pancreatoduodenectomy is the standard procedure for duodenal carcinoma of the third or fourth portion. As an alternative option, we developed a novel segmental resection (SR) with partial mesopancreatic and mesojejunal excision (pMME) that enhances radicality. In this report, the surgical technique with video and outcomes are described.

Method: We performed SR with pMME on seven consecutive patients with third or fourth duodenal carcinoma between 2009 and 2021. We divided the procedure into four sections, including (1) wide Kocher's maneuver, (2) supracolic anterior artery-first approach, (3) dissection of the mesopancreas and mesojejunum, and (4) devascularization of the uncinate process and dissection of duodenum.

Result: Median operative time was 348 min (range, 222-391 min), and median blood loss was 100 mL (range, 30-580 mL). Major complications of Clavien-Dindo classification grade 3a or more occurred in one patient. All patients achieved R0 resections with 10 mm or more proximal margin. Six cases (85%) were alive without recurrence.

Conclusion: We developed a radical and safe procedure of SR with pMME as an alternative and less invasive approach for duodenal carcinoma of the third or fourth portion.
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http://dx.doi.org/10.1007/s00423-022-02569-7DOI Listing
May 2022

A case of delayed foreshortening and disconnection of pipeline embolization device detected by chronological cone-beam computed tomography fusion image.

Acta Neurochir (Wien) 2022 Aug 24;164(8):2203-2206. Epub 2022 May 24.

Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Objective: The morphological changes of the pipeline embolization device (PED; Medtronic, Minneapolis, MN, USA), such as delayed migration or foreshortening, can relate to the incomplete occlusion of aneurysms.

Case Presentation: A 30-year-old man with a giant cavernous carotid artery aneurysm was treated with two PEDs using the overlapping technique. Six months after treatment, follow-up angiography showed morphological changes of the PEDs and residual flow into the aneurysm. Chronological cone-beam computed tomography fusion imaging clearly revealed the dynamic foreshortening of the first PED and the disconnection of both PEDs, so we decided to implant an additional PED.

Conclusion: This case illustrates that a three-dimensional understanding can be useful for assessing the cause of treatment failure or recurrence.
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http://dx.doi.org/10.1007/s00701-022-05245-3DOI Listing
August 2022

Outcomes of pancreatic cancer with liver oligometastasis.

J Hepatobiliary Pancreat Sci 2022 May 20. Epub 2022 May 20.

Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: Liver oligometastatic pancreatic cancer (PC) may have favorable outcomes. This study aims to evaluate outcomes and factors associated with overall survival (OS) of these patients.

Methods: We retrospectively investigated consecutive PC patients with liver metastasis treated at our institution between 2013 and 2020. Clinical characteristics and outcomes were compared and analyzed according to the extent of liver metastasis. Cox proportional hazards model was used to identify prognostic factors for OS.

Results: A total of 417 patients were included (multi-organ metastasis/polymetastasis/oligometastasis 174/158/85). Oligometastasis showed a longer OS compared to other types of metastases (7.7 vs 8.2 vs 13.1 months). Age <70 years, performance status of 0, modified Glasgow prognostic score of 0, carbohydrate antigen 19-9 <1000 U/mL were identified as significant prognostic factors for OS. A prognostic index consisting of these four factors successfully stratified the prognosis of these patients (prognostic index; high vs low, 19.9 vs 8.3 months). Highly selected patients who underwent surgical resection showed a median OS of 54.6 months.

Conclusions: Oligometastasis presented a relatively favorable outcome. Our new prognostic index was useful in stratifying the prognosis of these patients. Multimodal treatment including surgery may have additional survival benefits for highly selected patients.
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http://dx.doi.org/10.1002/jhbp.1184DOI Listing
May 2022

Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma.

Hepatology 2022 May 14. Epub 2022 May 14.

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.

Background And Aims: Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC.

Approaches And Results: We performed RNA-seq of tumor tissues in 113 patients with nonviral HCC and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into three molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with cadherin-associated protein beta 1 (CTNNB1) mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-β signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Patients with steatotic HCC, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti-PD-L1 and anti-VEGF antibodies.

Conclusions: Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.
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http://dx.doi.org/10.1002/hep.32573DOI Listing
May 2022

KRAS variant allele frequency, but not mutation positivity, associates with survival of patients with pancreatic cancer.

Cancer Sci 2022 May 14. Epub 2022 May 14.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

KRAS mutation is a major driver of pancreatic carcinogenesis and will likely be a therapeutic target. Due to lack of sensitive assays for clinical samples of pancreatic cancer with low cellularity, KRAS mutations and their prognostic association have not been fully examined in large populations. In a multi-institutional cohort of 1162 pancreatic cancer patients with formalin-fixed paraffin-embedded tumor samples, we undertook droplet digital PCR (ddPCR) for KRAS codons 12/13/61. We examined detection rates of KRAS mutations by clinicopathological parameters and survival associations of KRAS mutation status. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed using the Cox regression model with adjustment for potential confounders. KRAS mutations were detected in 1139 (98%) patients. The detection rate did not differ by age of tissue blocks, tumor cellularity, or receipt of neoadjuvant chemotherapy. KRAS mutations were not associated with DFS or OS (multivariable HR comparing KRAS-mutant to KRAS-wild-type tumors, 1.04 [95% CI, 0.62-1.75] and 1.05 [95% CI, 0.60-1.84], respectively). Among KRAS-mutant tumors, KRAS variant allele frequency (VAF) was inversely associated with DFS and OS with HRs per 20% VAF increase of 1.27 (95% CI, 1.13-1.42; p  <0.001) and 1.31 (95% CI, 1.16-1.48; p  <0.001), respectively. In summary, ddPCR detected KRAS mutations in clinical specimens of pancreatic cancer with high sensitivity irrespective of parameters potentially affecting mutation detections. KRAS VAF, but not mutation positivity, was associated with survival of pancreatic cancer patients.
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http://dx.doi.org/10.1111/cas.15398DOI Listing
May 2022

Diagnostic performance of fractional flow reserve derived from computed tomography in stented coronary arteries.

J Cardiovasc Comput Tomogr 2022 Jul-Aug;16(4):358-361. Epub 2022 Apr 28.

Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan.

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http://dx.doi.org/10.1016/j.jcct.2022.04.002DOI Listing
July 2022

Transcriptome of sessile serrated adenoma/polyps is associated with MSI-high colorectal cancer and decreased expression of CDX2.

Cancer Med 2022 May 10. Epub 2022 May 10.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

The objective of this study was to elucidate the molecular background of sessile serrated adenoma/polyp (SSA/P) endoscopically resected with comprehensive gene expression analysis. Gene expression profiling was performed for 10 tumor-normal pairs of SSA/P. Cluster analysis, gene set enrichment analysis (GSEA), and consensus molecular subtype (CMS) classification of colorectal cancer (CRC) were applied to our transcriptome analysis. Unsupervised cluster analysis showed that the gene expression profile of SSA/Ps is different from that of adjacent normal epithelial cells, even in the very early stage of tumorigenesis. According to the CMS classification, our microarray data indicated that SSA/Ps were classified as CMS1. GSEA demonstrated a strong association between SSA/P and microsatellite instability-high (MSI-H) CRC (p < 10 ). Transcriptome analysis of five MSI-related genes (MSH2, MSH6, MLH1, PMS1, and PMS2) and five CRC-related genes (BRAF, KRAS, APC, TP53, and CDX2) showed that CDX2 expression was most severely decreased in SSA/P. Immunohistochemical staining confirmed that CDX2 protein was reduced compared with the surrounding mucosa. Direct sequencing of the BRAF gene showed that the BRAF V600E mutation was detected in only nine of 36 cases. In a mouse model, BRAF, APC, or CDX2 deficiency indicated that the gene expression pattern with loss of CDX2 is more similar to our SSA/Ps compared with those induced by BRAF or APC mutation. Transcriptome analysis of SSA/Ps showed characteristic gene expression with a strong resemblance to MSI-H CRC. Downregulation of CDX2 expression is an essential molecular mechanism involved in the initial stage of SSA/P tumorigenesis. (UMIN000027365).
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http://dx.doi.org/10.1002/cam4.4810DOI Listing
May 2022

Decreased ARG1 expression as an adverse prognostic phenotype in non-alcoholic non-virus-related hepatocellular carcinoma.

Virchows Arch 2022 Aug 23;481(2):253-263. Epub 2022 Apr 23.

Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.

The incidence of non-alcoholic non-virus-related hepatocellular carcinoma (NANV-HCC) is increasing along with the growing prevalence of metabolic disorders. In this subset, few useful biomarkers are available to narrow down the high-risk group for recurrence. This study aimed to evaluate the prognostic impact of decreased ARG1 (arginase-1), which is pathologically known as a marker reflecting hepatocyte differentiation, in NANV-HCC. Besides, its relationship with biliary/progenitor cell markers, whose expressions are associated with poor prognosis, was also assessed. To reveal the clinicopathological association of decreased ARG1 expression in NANV-HCC, we investigated 99 patients who underwent curative-intent hepatectomy for NANV-HCC. Tissue microarrays were employed for immunohistochemical analysis. A total of 21 NANV-HCC cases (21%; 21/99) showed decreased ARG1 expression. Decreased ARG1 expression was an independent prognostic factor for both poor DFS (hazard ratio 2.17; 95% confidence interval 1.15-4.09; p = 0.02) and OS (hazard ratio 4.09; 95% confidence interval 1.71-9.80; p = 0.002). In addition, decreased ARG1 expression was significantly associated with expressions of biliary/progenitor cell markers, CK19 and CD56 (p < 0.01). As cytologic features of tumor cells, decreased ARG1 expression was significantly associated with lipid-less cytologic morphology (p = 0.045). These findings indicate that decreased ARG1 expression is a predictive phenotype of postoperative recurrence with poor prognosis in patients with NANV-HCC. Decreased ARG1 expression may be a precursor or overlapping feature with biliary/progenitor cell marker expressions in NANV-HCC.
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http://dx.doi.org/10.1007/s00428-022-03318-3DOI Listing
August 2022

Early-onset pancreatic cancer: Clinical characteristics and survival outcomes.

Pancreatology 2022 May 7;22(4):507-515. Epub 2022 Apr 7.

Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. Electronic address:

Background: Early-onset pancreatic cancer (≤50 years, EOPC) is uncommon. This study aims to characterize the clinical and survival characteristics of EOPC in comparison to late-onset pancreatic cancer (>50 years, LOPC).

Methods: We retrospectively investigated consecutive PC patients treated at our institution between 2010 and 2019. We analyzed and compared clinicopathological characteristics, treatments, and outcomes of EOPC and LOPC.

Results: Of 1646 PC patients identified (768 resectable/borderline resectable; 248 locally advanced; 630 metastatic), 127 (8%) had EOPC. Current smoking and heavy drinking were associated with EOPC. EOPC presented at a more advanced stage and had higher neutrophil-to-lymphocyte ratios than LOPC. Survival outcomes were similar between the two groups, both in the entire cohort and in each resectability group. In patients undergoing resection, EOPC tended to have a higher N stage (p = 0.099) and had a higher pathological stage (stage IV, 20% vs. 7%, p = 0.005) and a lower rate of macroscopically curative resection (80% vs. 93%, p = 0.006). Liver recurrence was more commonly observed in EOPC (42% vs. 23%, p = 0.015). In the metastatic cohort, combination chemotherapy regimens were more frequently administered in EOPC as first-line treatment (79% vs. 64%, p = 0.028). Both median PFS (4.4 vs. 5.3 months, p = 0.647) and OS (11.5 vs. 9.5 months, p = 0.183) were not significantly different between the two groups.

Conclusions: EOPC presented with a more aggressive tumor biology. Survival outcomes were similar to LOPC due to more intensive treatment.
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http://dx.doi.org/10.1016/j.pan.2022.04.003DOI Listing
May 2022

Prevalence and outcomes of stent thrombosis with in-stent calcified nodules: substudy from the REAL-ST registry.

EuroIntervention 2022 Apr 8. Epub 2022 Apr 8.

Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: The relationship between in-stent calcified nodules (IS-CN) and second-generation drug-eluting stent (G2-DES) stent thrombosis (ST) remains uncertain.

Aims: We aimed to evaluate the prevalence, clinical demographic and long-term clinical outcomes after G2-DES ST with IS-CN.

Methods: The prespecified substudy of the REAL-ST registry (a retrospective, multicentre registry of patients with definite ST after first- and G2-DES implantation) enrolled patients who experienced definite G2-DES ST and who underwent pre-intervention intravascular ultrasound imaging at index ST events.

Results: IS-CN was observed in 15 out of 118 (13%) definite G2-DES ST cases. The multiple logistic regression model demonstrated that haemodialysis (odds ratio [OR] 12.27, 95% confidence interval [CI]: 1.56-94.54; p=0.02), proximal or mid-right coronary artery lesions (OR 12.79, 95% CI: 1.78-92.13; p=0.01) and severe calcification (OR 13.01, 95% CI: 1.18-142.94; p=0.04) were independently associated with ST with IS-CN. The cumulative 5-year incidence of target lesion revascularisation (TLR) after ST was significantly higher in the IS-CN group than in the non-IS-CN group (p=0.02). Independent predictors of TLR after the index ST events were female sex (hazard ratio [HR] 3.05, 95% CI: 1.20-7.74; p=0.02), diabetes mellitus (HR 3.26, 95% CI: 1.26-8.41; p=0.01) and IS-CN (HR 3.07, 95% CI: 1.16-8.14; p=0.02).

Conclusions: IS-CN may be one of the underlying mechanisms of G2-DES ST. Notably, IS-CN was associated with a higher TLR rate after the index ST events, suggesting the need for careful clinical follow-up of ST patients with IS-CN.
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http://dx.doi.org/10.4244/EIJ-D-21-00976DOI Listing
April 2022

The natural history of sporadic non-ampullary duodenal epithelial tumors: Can we wait and see?

DEN open 2021 Apr 21;1(1):e9. Epub 2021 Apr 21.

Department of Gastroenterology Graduate School of Medicine The University of Tokyo Tokyo Japan.

Objectives: The natural history of sporadic non-ampullary duodenal epithelial tumors (SNADETs) is poorly documented. The aim of this study was to evaluate the history of SNADETs in patients where immediate resection could not be performed.

Methods: This is a single-center retrospective study of 86 consecutive cases of SNADETs who did not undergo immediate resection and were followed-up with upper gastrointestinal endoscopy for more than 6 months.

Results: During a follow-up period of 36.8 (6.0-613.0) months, macroscopic progression was admitted in eight (9.3%). Of these, the final histology in four was adenocarcinoma, and three cases demonstrated submucosal invasion. Rates of macroscopic progression at 150 months after detection were 11.1%, 16.7%, and 30.0% for SNADETs <5 mm, <10 mm, and ≥10 mm, respectively.

Conclusion: The overall risk of SNADETs progressing to invasive cancer is low. However, changes in macroscopic size or shape of SNADETs signify a high risk of progression to invasive cancer.
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http://dx.doi.org/10.1002/deo2.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8828177PMC
April 2021

Efficacy of myocardial washout of Tc-MIBI/Tetrofosmin for the evaluation of inflammation in patients with cardiac sarcoidosis: comparison with F-fluorodeoxyglucose positron emission tomography findings.

Ann Nucl Med 2022 Jun 18;36(6):544-552. Epub 2022 Mar 18.

Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Objective: Both myocardial perfusion scintigraphy and F-fluorodeoxyglucose positron emission tomography (FDG PET) are useful for the diagnosis of cardiac sarcoidosis (CS). However, the association between the washout of Tc-labeled tracer and FDG PET has not been established. This study aimed to evaluate the association between the washout of Tc-labeled tracer and FDG PET findings in patients with CS.

Methods: We retrospectively analyzed 64 patients (65.0 ± 11.2 years, 53% male) with suspected CS who underwent myocardial single-photon emission computed tomography (SPECT) with Tc-labeled tracer and FDG PET. The SPECT images were acquired at 15 min (early images) and 3 h (delayed images) after injection and scored visually using a 17-segment model with a 5-point scoring system. The washout score was defined as the difference between the early and delayed total defect scores. FDG positivity was considered as focal or focal on diffuse patterns on visual assessment, and FDG uptake was quantified by measuring the standardized uptake value (SUV) of each of the 17 segments.

Results: The washout score was significantly higher for the CS group than for the non-CS group (3.0 [-1.0-5.0] vs. 0.0 [-0.5-1.0], p = 0.010). Receiver operating characteristic analysis showed that a washout score of ≥ 2 had the best accuracy for detecting CS (88% sensitivity and 56% specificity) and FDG positivity (71% sensitivity and 89% specificity). In the segment-based analysis of 833 segments from 49 patients, excluding 15 patients with diffuse FDG uptake, the median SUVs for FDG uptake for the washout scores of ≤ 0, 1, and 2 were 2.3 (1.8-3.6), 4.2 (2.9-7.8), and 8.3 (6.5-9.4), respectively (p < 0.001).

Conclusions: The washout of Tc-labeled tracer can be a useful marker for the evaluation of FDG PET findings in patients with CS.
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http://dx.doi.org/10.1007/s12149-022-01735-7DOI Listing
June 2022

Optimizing Indications for Conversion Surgery Based on Analysis of 454 Consecutive Japanese Cases with Unresectable Pancreatic Cancer Who Received Modified FOLFIRINOX or Gemcitabine Plus Nab-paclitaxel: A Single-Center Retrospective Study.

Ann Surg Oncol 2022 Aug 16;29(8):5038-5050. Epub 2022 Mar 16.

Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: The prognosis of initially unresectable pancreatic cancer (UR-PC) has improved since the introduction of FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GNP) treatment. Nonetheless, the indications and optimal timing for conversion to resection remain unclear for UR-PC. The aim of this study is to evaluate the characteristics of cases with initially UR-PC who received modified FFX or GNP treatment.

Methods: This retrospective study reviewed 454 consecutive Japanese UR-PC cases who received modified FFX/GNP treatment. Cases were categorized according to resection status, and overall survival (OS) was evaluated using a multivariable prognostic scoring model (0-4 points, higher score indicating more favorable prognostic factors).

Results: The overall resection rate was 16% for locally advanced UR-PC (UR-LA) and 5% for metastatic UR-PC (UR-M). The resection group had better OS than the nonresection group (median OS time: not reached versus 13.0 months, P < 0.001). The independent prognostic factors were normalized CA19-9 concentration, modified Glasgow prognostic score of 0, tumor shrinkage after chemotherapy, chemotherapy duration ≥ 8 months, and resection. Cases were grouped according to their prognostic score, and the results suggested that candidates for resection might have prognostic scores of 4 points in UR-M cases or 2-4 points in UR-LA cases.

Conclusions: Stratification according to prognostic score was useful in predicting the outcomes of UR-PC cases and may aid in identifying cases who might benefit from surgical treatment after responding to chemotherapy.
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http://dx.doi.org/10.1245/s10434-022-11503-6DOI Listing
August 2022

Proposal of new treatment algorithm for gastric cancer liver metastases: Up-front surgery or conversion surgery?

Glob Health Med 2022 Feb;4(1):57-60

Department of Surgery, Hepato-Biliary Pancreatic Surgery Division, National Center for Global Health and Medicine, Tokyo, Japan.

Hepatectomy for gastric cancer liver metastases (GCLM) has a 5-year survival rate of 9-42%; however, indications for hepatectomy remain unclear. Many researchers have reported prognostic factors for GCLM after hepatectomy, but surgical indications vary according to the literature. Furthermore, the indication for optimal candidates for neoadjuvant chemotherapy and intensive chemotherapy is also unclear. To understand the indications for surgery and chemotherapy intended for hepatectomy for GCLM, a new treatment algorithm was created based on previously reported evidence from the viewpoint of hepatic surgeons.
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http://dx.doi.org/10.35772/ghm.2021.01102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8884038PMC
February 2022

ASO Author Reflections: Histology-Based Supervised Machine Learning Model Can Predict Recurrence Pattern of Pancreatic Cancer.

Ann Surg Oncol 2022 Mar 12. Epub 2022 Mar 12.

Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.

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http://dx.doi.org/10.1245/s10434-022-11540-1DOI Listing
March 2022

Histone arginine methyltransferase CARM1 selective inhibitor TP-064 induces apoptosis in endometrial cancer.

Biochem Biophys Res Commun 2022 04 23;601:123-128. Epub 2022 Feb 23.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.

Histone modification is the key epigenetic mechanism that regulates gene expression. Coactivator-associated arginine methyltransferase 1 (CARM1) is an arginine methyltransferase that catalyzes dimethylation of histone H3 (H3R17) at arginine 17. Lately, it has been suggested that CARM1 is associated with human carcinogenesis, and the CARM1-selective inhibitor, TP-064, has been shown to be a potential therapeutic agent for multiple myeloma. However, the physiological significance of CARM1 in endometrial cancer remains unclear. Therefore, we aimed to explore the role of CARM1 and the effect of TP-064 in endometrial cancer. To this end, we analyzed CARM1 expression in endometrial cancer using quantitative real-time polymerase chain reaction and examined the antitumor mechanism with CARM1 knockdown endometrial cancer cells. Moreover, we evaluated the therapeutic capability of TP-064 in endometrial cancer cells. CARM1 was remarkably overexpressed in 52 endometrial cancer tissues compared to normal endometrial tissues. The growth of CARM1 knockdown endometrial cancer cells was suppressed and CARM1 knockdown induced apoptosis. TP-064 also inhibited endometrial cancer cell growth and declined the number of endometrial cancer cell colonies. These data suggest that CARM1 may be a powerful therapeutic target for endometrial cancer.
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http://dx.doi.org/10.1016/j.bbrc.2022.02.086DOI Listing
April 2022
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