Death-Associated Protein Kinase 1 (DAPK1) Protects against Myocardial Injury Induced by Myocardial Infarction in Rats via Inhibition of Inflammation and Oxidative Stress

Article

作者: Jiang, Xiaojing ; Zhang, Jun ; Zhang, Jing ; Zhou, Bo ; Zhang, Zhenzhen ; Tang, Yanrong

Objective. Heart failure and ventricular remodeling after acute myocardial infarction (AMI) are important factors affecting the prognosis of patients. Therefore, we expected to explore the therapeutic target of AMI by studying the effect of death-associated protein kinase 1 (DAPK1) on AMI rat model. Materials and Methods. We used male Sprague-Dawley rats to make AMI model, and after 1, 3, 7, and 14 d, we detect the success rate of modeling and the expression change of DAPK1 through 2, 3, 5-triphenyl tetrazolium chloride staining, myocardial injury markers detection, echocardiographic detection, and histological experiment. In addition, we determined the effect of DAPK1 on AMI by subcutaneous injection of the DAPK1 inhibitor (TC-DAPK 6). The effect of DAPK1 on cardiomyocytes has also been verified in cell experiments on H9c2 cells. Results. The expression of DAPK1 in AMI rats was significantly higher than that in sham group, and it increased with time. The expression of inflammatory factors (interleukin- (IL-) 1β, IL-6, and tumor necrosis factor-α) in AMI rats treated by TC-DAPK 6 was reduced. In addition, TC-DAPK 6 also reduced the activity of malonaldehyde and increased the activities of superoxide dismutase, glutathione, and catalase. The expression of antioxidant molecules such as peroxiredoxin1/4 and glutathione peroxidase1/3 was also promoted by TC-DAPK 6. In H9c2 cells, TC-DAPK 6 also reduced its oxidative stress level. Conclusions. The increase of DAPK1 may be related to the pathogenesis of AMI. DAPK1 inhibitors protect cardiomyocytes from AMI-induced myocardial injury by reducing levels of inflammation and oxidative stress in myocardial tissue and cells.

2021-04-01·Journal of Nuclear Medicine1区 · 医学

Phase I Study of ^99mTc-ADAPT6, a Scaffold Protein–Based Probe for Visualization of HER2 Expression in Breast Cancer

1区 · 医学

Article

作者: Vorobyeva, Anzhelika ; Tolmachev, Vladimir ; Garousi, Javad ; Sandström, Mattias ; Zelchan, Roman ; Medvedeva, Anna ; Bragina, Olga ; Orlova, Anna ; Lindbo, Sarah ; Tarabanovskaya, Natalya ; Sörensen, Jens ; Chernov, Vladimir ; Hober, Sophia ; von Witting, Emma ; Doroshenko, Artem ; Borin, Jesper

Radionuclide molecular imaging of human epidermal growth factor receptor type 2 (HER2) expression may help to stratify breast and gastroesophageal cancer patients for HER2-targeting therapies. Albumin-binding domain-derived affinity proteins (ADAPTs) are a new type of small (46-59 amino acids) protein useful as probes for molecular imaging. The aim of this first-in-humans study was to evaluate the biodistribution, dosimetry, and safety of the HER2-specific ^99mTc-ADAPT6. Methods: Twenty-nine patients with primary breast cancer were included. In 22 patients with HER2-positive (n = 11) or HER2-negative (n = 11) histopathology, an intravenous injection of 385 ± 125 MBq of ^99mTc-ADAPT6 was performed, randomized to an injected protein mass of either 500 μg (n = 11) or 1,000 μg (n = 11). Planar scintigraphy followed by SPECT imaging was performed after 2, 4, 6, and 24 h. An additional cohort (n = 7) was injected with 165 ± 29 MBq (injected protein mass, 250 μg), and imaging was performed after 2 h only. Results: Injections of ^99mTc-ADAPT6 were well tolerated at all mass levels and not associated with adverse effects. ^99mTc-ADAPT6 cleared rapidly from the blood and most other tissues. The normal organs with the highest accumulation were the kidney, liver, and lung. Effective doses were 0.009 ± 0.002 and 0.010 ± 0.003 mSv/MBq for injected protein masses of 500 and 1,000 μg, respectively. Injection of 500 μg resulted in excellent discrimination between HER2-positive and HER2-negative tumors as early as 2 h after injection (tumor-to-contralateral breast ratio, 37 ± 19 vs. 5 ± 2; P < 0.01). The tumor-to-contralateral breast ratios for HER2-positive tumors were significantly (P < 0.05) higher for an injected mass of 500 μg than for either 250 or 1,000 μg. Conclusion: Injections of ^99mTc-ADAPT6 are safe and associated with low absorbed and effective doses. A protein dose of 500 μg is preferable for discrimination between tumors with high and low expression of HER2. Further studies are justified to evaluate whether ^99mTc-ADAPT6 can be used as an imaging probe to stratify patients for HER2-targeting therapy in areas where PET imaging is not readily available.

2020-04-01·Breast Cancer Research and Treatment2区 · 医学

A randomized study comparing docetaxel/cyclophosphamide (TC), 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by TC, and TC followed by FEC for patients with hormone receptor-positive HER2-negative primary breast cancer

2区 · 医学

Article

作者: Tanaka-Mizuno, Sachiko ; Higaki, Kenji ; Takahashi, Masato ; Ishiguro, Hiroshi ; Takano, Toshimi ; Matsunami, Nobuki ; Yanagita, Yasuhiro ; Mizutani, Makiko ; Kaneko, Koji ; Sato, Nobuaki ; Ohno, Shinji ; Yamamoto, Yutaka ; Ohtani, Shoichiro ; Fujisawa, Tomomi ; Kadoya, Takayuki ; Masuda, Norikazu ; Morita, Satoshi ; Morimoto, Takashi ; Toi, Masakazu

AbstractPurposeOur primary objective was to determine the benefit/risk of anthracycline-free regimens by comparing docetaxel + cyclophosphamide (TC) alone, fluorouracil + epirubicin + cyclophosphamide (FEC) followed by TC, or TC followed by FEC as a primary treatment for patients with HR-positive, HER2-negative BC.MethodsWe randomized patients with stage I–III HR-positive HER2-negative, operable BC to receive either six cycles of TC (TC6), three cycles of FEC followed by three cycles of TC (FEC-TC), or three cycles of TC followed by three cycles of FEC (TC-FEC). The primary endpoint was the pathological response. Secondary endpoints included clinical response, type of surgical procedure, recurrence, death, and adverse events (by NCI-Common Terminology Criteria for Adverse Events v.3.0). We conducted all statistical analyses using SAS Version 9.2.ResultsWe enrolled 195 patients and analyzed data from 193 as the intention-to-treat population. Pathological complete response rates were numerically higher in the TC6 group than in the other groups (p = 0.321). The breast conservation rate was significantly higher in the TC6 group (73%) than in the other groups (FEC-TC 51%, TC-FEC 45%, p = 0.007). Adverse events with grade > 3 were not common in the treatment groups (p = 0.569). The overall and distant disease-free survivals were similar among the groups with median follow-up of 5.80 years.ConclusionsDespite similar long-term efficacy and safety profile, the higher breast conservation rate in the TC6 group suggests that preoperative chemotherapy without an anthracycline may benefit patients with HR-positive HER2-negative BC.Trial registrationUMIN000003283 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003873.

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