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1.
Interv Radiol (Higashimatsuyama) ; 8(3): 169-172, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-38020461

RESUMO

Purpose: We aim to evaluate retrospectively the feasibility, safety, and initial therapeutic outcomes of radiofrequency ablation combined with hepatic artery embolization using a tris-acryl gelatin microsphere for colorectal liver metastases. Material and Methods: Six consecutive patients (4 men and 2 women) with median age of 68 years (range 57-78 years) underwent computed tomography fluoroscopy-guided radiofrequency ablation immediately after hepatic artery embolization using microspheres. This study evaluated tumor visibility on noncontrast-enhanced computed tomography immediately after hepatic artery embolization; analyzed local tumor progression; defined technical success as the coverage of the tumor by the ablative zone; and assessed adverse events based on Common Terminology Criteria for Adverse Events v5.0. Results: Ten tumors with median maximum diameter of 9 mm (range 5-52 mm) were treated in nine sessions. Eight tumors (80%, 8/10 tumors) were detected as high-attenuation nodules. One tumor was treated in two sessions because follow-up computed tomography revealed an insufficient ablative margin. Therefore, the primary and secondary technical success was 90% (9/10 tumors) and 100% (10/10 tumors), respectively. Grade 2 pneumothorax was observed in one session (11%, 1/9 sessions). No grade 3 or higher adverse event was observed. The local tumor progression rate was 20% (2/10 tumors) during the median follow-up of 14 months. Conclusions: Radiofrequency ablation following microsphere embolization may be a feasible, safe, and useful therapeutic option for controlling small colorectal liver metastases.

2.
In Vivo ; 37(5): 2237-2243, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37652495

RESUMO

BACKGROUND/AIM: This is a retrospective evaluation of whether percutaneous direct puncture biopsy of lung lesions contacting to the pleura is justified. PATIENTS AND METHODS: Between August 2016 and July 2021, 163 consecutive patients (100 males, 63 females with a median age of 73 years) who had malignant lung tumors measuring 0.6-12.4 cm (median, 2.9 cm) that contacted to the pleura and underwent percutaneous lung biopsy under computed tomography fluoroscopic guidance using an 18-gauge end-cut needle were examined. The trajectory was direct puncture in 80 patients (49.1%, 80/163), and trans-lung in 83 patients (50.9%, 83/163). Diagnostic yield and major adverse event rates of direct and trans-lung puncture biopsies were compared. RESULTS: No difference was found in diagnostic yield between direct puncture and trans-lung biopsies (93.8% vs. 98.8%, p=0.11). Major adverse events were major pneumothorax (n=13/163, 8.0%), pleural dissemination (n=18/163, 11.0%), and hemothorax requiring arterial embolization (n=1/163, 1.0%). Direct puncture caused major pneumothorax significantly less than trans-lung puncture did (0%, 0/80 vs. 15.7%, 13/83, p<0.001). No significant difference was found between the two biopsy methods regarding the incidence of pleural dissemination (11.0%, 11/80 vs. 8.4%, 7/83, p=0.32). CONCLUSION: Direct puncture biopsy of malignant lung tumors contacting to the pleura is justified.


Assuntos
Neoplasias Pulmonares , Pneumotórax , Masculino , Feminino , Humanos , Idoso , Pleura , Pneumotórax/etiologia , Pneumotórax/epidemiologia , Pneumotórax/patologia , Estudos Retrospectivos , Neoplasias Pulmonares/complicações , Biópsia por Agulha/efeitos adversos , Pulmão/patologia
3.
Interv Radiol (Higashimatsuyama) ; 8(2): 80-82, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37485482

RESUMO

When a 66-year-old man with hepatocellular carcinoma underwent an angiographic examination, a 4-Fr catheter was inserted from the right femoral artery. It became tightly knotted in the descending aorta. To untangle the knotted catheter, a noncompliant balloon catheter was delivered into the knotted loop from the contralateral femoral artery. After the balloon catheter was inflated from the inside of the knotted loop, the knot became loose. Finally, the knotted catheter was untangled. Subsequently, the remainder of the examination was performed as initially planned.

4.
In Vivo ; 37(4): 1816-1821, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37369519

RESUMO

BACKGROUND/AIM: To evaluate retrospectively whether bland embolization using microspheres is safe and useful for relieving pain in patients with painful malignant musculoskeletal (MSK) tumors. PATIENTS AND METHODS: Bland embolization using microspheres was performed for 20 patients (11 women/9 men) with a median age of 69 years (range=40-89 years) who had 22 painful malignant MSK tumors. The maximum tumor diameters were 2.4-13.8 cm (median, 7.5 cm). Pain was evaluated using the visual analog scale. A decrease of this score by 2 or more after embolization was defined as clinically effective pain relief. Adverse events (AEs) were evaluated using CTCAE v5.0. Objective response, disease control rates, and overall survival were also evaluated. RESULTS: Effective pain relief was achieved in 18 patients (90.0%, 18/20). Grade-3 AEs developed in four patients (20.0%, 4/20): skin ulcer (n=2), skin ulcer and pain (n=1), and muscle weakness with dysesthesia (n=1). No grade-4 or grade-5 AEs developed. Objective response and disease control rates were 26.7% (4/15) and 86.7% (13/15), respectively. The 1-year survival rate was 43.8%, with median survival of 9.2 months (range=0.5-41.0 months). CONCLUSION: Although the survival benefit is equivocal, bland embolization is acceptably safe and useful for relieving pain by controlling tumor growth in patients with painful malignant MSK tumors.


Assuntos
Neoplasias Hepáticas , Masculino , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Microesferas , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias Hepáticas/patologia , Dor/etiologia
5.
Cardiovasc Intervent Radiol ; 46(6): 770-776, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37188896

RESUMO

PURPOSE: To evaluate, experimentally and clinically, the radioprotective effects of a semicircular X-ray shielding device for operators during CT fluoroscopy-guided IR procedures. MATERIALS AND METHODS: During experimentation, the reduction rates of scattered radiation rates from CT fluoroscopy were evaluated using a humanoid phantom. Two shielding device positions were tested: "shielding close to the CT gantry" and "shielding close to the operator". The scattered radiation rate without shielding was also evaluated. The clinical study retrospectively evaluated the operator's radiation exposure during 314 CT-guided IR procedures. With a semicircular X-ray shielding device (with shielding group, n = 119) or without it (no shielding group, n = 195), CT fluoroscopy-guided IR procedures were performed. Radiation dose measurements were taken using a pocket dosimeter placed near the operator's eye. For shielding and no shielding groups, the procedure time, dose length product (DLP), and the operator's radiation exposures were compared. RESULTS: Experimentation revealed the respective mean reduction rates of "shielding close to the CT gantry" and "shielding close to the operator" as 84.3% and 93.5% compared with the no-shielding setting. Although no significant differences were found in the procedure time and the DLP between "no shielding" and "with shielding" groups in the clinical study, the operators' radiation exposure in the "with shielding" group (0.03 ± 0.04 mSv) was significantly lower than in the "no shielding" group (0.14 ± 0.15 mSv; p < .001). CONCLUSION: The semicircular X-ray shielding device provides valuable radioprotective effects for operators during CT fluoroscopy-guided IR.


Assuntos
Exposição Ocupacional , Exposição à Radiação , Humanos , Doses de Radiação , Estudos Retrospectivos , Raios X , Exposição à Radiação/prevenção & controle , Fluoroscopia/métodos , Tomografia Computadorizada por Raios X , Exposição Ocupacional/prevenção & controle , Radiografia Intervencionista
6.
Life (Basel) ; 13(1)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36676174

RESUMO

Metastasis of hepatocellular carcinoma (HCC) in the pouch of Douglas is relatively rare. A 65-year-old man with liver cirrhosis was admitted for detailed examination of a pelvic tumor. He had a previous history of ruptured HCC, and received emergent hemostasis with transcatheter arterial embolization followed by curative ablation. His blood tests showed an increase in des-gamma-carboxy prothrombin (DCP). Contrast-enhanced computed tomography (CE-CT) revealed a heterogeneously enhanced large pelvic tumor, but no additional tumorous lesions were detected in other organs, including the lungs, liver and abdominal lymph nodes. The colonoscopy showed compression by an extra-luminal/submucosal tumor, and computed tomography-guided percutaneous needle biopsy revealed that the pelvic tumor was metastasis of HCC. Because of the poor liver function, the solitary pelvic tumor was treated with three-dimensional conformal radiation therapy (3D-CRT). The tumor size and the DCP value were markedly decreased after radiation therapy. Nine months later, occasional mild bloody stool due to radiation proctitis was observed; however, no serious side effects occurred. Our case suggests that radiation therapy may be a therapeutic option for a solitary metastatic lesion of HCC in the pouch of Douglas.

7.
Interv Radiol (Higashimatsuyama) ; 7(3): 93-99, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36483664

RESUMO

Purpose: To evaluate the feasibility, safety, and efficacy of radiofrequency (RF) ablation using an ablation system (arfa RF ABLATION SYSTEMⓇ; Japan Lifeline Co. Ltd.) for treating solid tumors in various organs. Material and Methods: Between October 2019 and August 2021, 80 patients (29 women, 51 men; median age, 70.0 yr) underwent 107 RF ablation sessions using the ablation system to treat 151 tumors in the liver (n = 86), lung (n = 51), adrenal gland (n = 4), pleura (n = 4), bone (n = 3), lymph node (n = 2), and kidney (n = 1). The maximum tumor diameter was 2-40 mm (median, 11 mm). This study evaluated technical success (defined as the completion of planned RF ablation), technique efficacy (defined as the complete tumor ablation on follow-up images), and adverse events. Local tumor progression in 146 curatively treated malignant tumors was evaluated. Results: The technical success rate was 100% (107/107). Ablation zones in two tumors were insufficient. Therefore, the primary technique efficacy rate was 98.1% (105/107). Grade 3 hepatic infarction (1.6%, 1/64) and grade 4 pleuritis (3.4%, 1/29) occurred respectively after liver and lung RF ablation. During the median follow-up period of 10.2 months (Interquartile range, 4.2 and 16.4 months), local tumor progression developed in two tumors (1.4%, 2/146). Conclusions: The arfa RF ABLATION SYSTEMⓇ is a feasible, safe, and effective RF ablation device for managing solid tumors in various organs.

8.
Interv Radiol (Higashimatsuyama) ; 7(1): 9-16, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35911873

RESUMO

Purpose: To clarify the utility of microballoon catheter in renal arterial ethanol embolization of renal angiomyolipoma (AML). Material and Methods: A total of 20 patients (15 women, 5 men) with median age of 45 years (39-60 years) underwent embolization to treat 22 AMLs. A mixture of ethanol and iodized oil was injected into the feeding arteries of 13 tumors using balloon occlusion (the balloon embolization group) with a microballoon catheter and 9 tumors without using balloon occlusion (the non-balloon embolization group). Changes in the maximum tumor diameter, tumor volume, and adverse events were evaluated. Result: The median baseline maximum tumor diameters and volumes were 6.3 cm and 61.4 cm3 in the balloon embolization group, and 4.6 cm and 40.1 cm3 in the non-balloon embolization group, respectively. Tumor enhancement disappeared on postembolization angiography in all cases. All tumors shrunk after embolization. There were no statistically significant differences in the percent decrease in the maximum tumor diameter and volume at 10-12 month between balloon occlusion group (31.5% and 67.9%) and control group (34.8% and 62.6%). Fever was significantly more frequent when balloon occlusion was used: 38% vs. 0% (p = 0.03). No major complication was observed in either patient group. Conclusions: Balloon occlusion may not affect tumor shrinkage when embolizing AMLs with a mixture of ethanol and lipiodol.

9.
Medicine (Baltimore) ; 100(34): e26681, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449453

RESUMO

RATIONALE: Recently, the number of osteosarcomas has been increasing in elderly patients due to human longevity. Lung metastases are the primary cause of death from osteosarcomas. Complete resection of lung metastases can prolong the survival. However, complete resection in elderly patients is often difficult due to high risk of operative complications. Computed tomography (CT) guided radiofrequency ablation (RFA) is a minimally invasive technique to destroy tumor nodules using heat. In this report, we present the first case older than 65 years applying RFA for lung metastases due to osteosarcoma. PATIENT CONCERNS: A 74-year-old male presented with 1-year history of heel pain. A conventional high-grade osteosarcoma in his calcaneus was diagnosed. Below-knee amputation was performed. However, lung metastases were found in both lungs 1 year after amputation. CT-guided lung RFA was chosen since surgical intervention for lung metastases was abandoned because of tumor multiplicity and medical comorbidities. A total of 18 lung metastases were treated by CT-guided RFA. The most frequent complication was pneumothoraxes in 4 of 8 (50%) procedures and chest tube drainage was required in 2 of these (2 of 8 (25%) procedures). DIAGNOSES: Six lung metastases of osteosaroma were found in both lungs at 1 year after surgery. INTERVENTIONS: CT-guided lung RFA was performed. A total of 18 lung metastases were treated in 8 lung RF procedures. OUTCOMES: The patient has been alive with disease for 5.5 years after the initial surgery. LESSONS: CT-guided lung RFA is effective for elderly patients with osteosarcoma lung metastases in spite of discouragement of lung metastasectomy due to multiplicity of metastases and medical-comorbidities.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Osteossarcoma/patologia , Ablação por Radiofrequência/métodos , Idoso , Calcâneo/patologia , Humanos , Masculino , Radiografia Intervencionista , Tomografia Computadorizada por Raios X
10.
Interv Radiol (Higashimatsuyama) ; 6(3): 108-111, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35912282

RESUMO

We describe the case of a 48-year-old woman who presented with traumatic rupture of a giant leiomyoma and massive hemoperitoneum caused by slipping and falling in the bathroom. She was in shock on arrival, and resuscitation was performed. Contrast-enhanced computed tomography showed massive intra-abdominal hematoma and extravasation from the subserous leiomyoma. Uterine artery embolization was performed, but she went into shock again after 6 h. The second contrast-enhanced computed tomography revealed persistence of extravasation. During 2nd UAE, an angiogram revealed extravasation originating from left round ligament artery. After the embolization of the left round ligament and bilateral uterine arteries, the patient recovered from shock. Total abdominal hysterectomy was performed on day 2 of admission to prevent re-bleeding and infection, then she discharged on day 19 of admission.

11.
Oncotarget ; 10(52): 5403-5411, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31534626

RESUMO

Objectives: To examine the prognostic value of interim 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) findings after 2-4 cycles of rituximab, plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL) receiving standardized treatment. Results: After a median 3.36 years (range 0.33 to 9.14 years), 24 of the 80 patients had documented relapse. In Interim-PET findings, 2-year PFS was significantly shorter for PET-positive as compared with PET-negative patients (50.0% vs. 86.4%; p = 0.0012). In End-PET findings, 2-year PFS was significantly shorter for PET-positive as compared with PET-negative patients (25.0% vs. 84.7%; p < 0.0001). The positive predictive value (PPV) and negative predictive value (NPV) of Interim-PET for predicting relapse or disease progression were 57.1% and 75.8%, respectively, while those for End-PET were 75.0% and 75.0%, respectively. Methods: Eighty DLBCL patients treated with first-line 6-8 R-CHOP courses regardless of interim imaging findings were enrolled. Each underwent FDG-PET/CT scanning at staging, and again during (Interim-PET) and at the end of (End-PET) therapy. PET positivity or negativity at Interim-PET and End-PET as related to progression-free survival (PFS) was examined using Kaplan-Meier analysis. Conclusion: Mid-treatment FDG-PET/CT findings may be useful for determining disease status in patients with DLBCL undergoing induction R-CHOP chemotherapy, though are not recommended for treatment decisions as part of routine clinical practice.

13.
Oxf Med Case Reports ; 2018(12): omy097, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30410777

RESUMO

Numb chin syndrome (NCS) is defined as reduced or absent sensation in an area of the chin and lower lip within the distribution of the mental or inferior alveolar nerves. The causes of NCS may be neoplastic, traumatic, dental, toxic, drug-induced, inflammatory, autoimmune or infectious. NCS may be the preliminary symptom of malignancy or recurrence/metastasis in patients with cancer. Therefore, the occurrence of NCS warrants careful examination and monitoring of such patients. This article presents two cases of NCS reported in a patient with prostate cancer and in a patient with Burkitt lymphoma/leukaemia.

14.
Sci Rep ; 8(1): 6423, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29686309

RESUMO

The dual function of runt-related transcriptional factor 1 (RUNX1) as an oncogene or oncosuppressor has been extensively studied in various malignancies, yet its role in gastric cancer remains elusive. Up-regulation of the ErbB2/HER2 signaling pathway is frequently-encountered in gastric cancer and contributes to the maintenance of these cancer cells. This signaling cascade is partly mediated by son of sevenless homolog (SOS) family, which function as adaptor proteins in the RTK cascades. Herein we report that RUNX1 regulates the ErbB2/HER2 signaling pathway in gastric cancer cells through transactivating SOS1 expression, rendering itself an ideal target in anti-tumor strategy toward this cancer. Mechanistically, RUNX1 interacts with the RUNX1 binding DNA sequence located in SOS1 promoter and positively regulates it. Knockdown of RUNX1 led to the decreased expression of SOS1 as well as dephosphorylation of ErbB2/HER2, subsequently suppressed the proliferation of gastric cancer cells. We also found that our novel RUNX inhibitor (Chb-M') consistently led to the deactivation of the ErbB2/HER2 signaling pathway and was effective against several gastric cancer cell lines. Taken together, our work identified a novel interaction of RUNX1 and the ErbB2/HER2 signaling pathway in gastric cancer, which can potentially be exploited in the management of this malignancy.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Receptor ErbB-2/metabolismo , Transdução de Sinais/fisiologia , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Subunidade alfa 2 de Fator de Ligação ao Core/antagonistas & inibidores , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Relação Dose-Resposta a Droga , Humanos , Proteína SOS1/metabolismo , Neoplasias Gástricas/patologia , Regulação para Cima
15.
Blood Adv ; 2(5): 509-515, 2018 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-29500219

RESUMO

Although the function of Runt-related (RUNX) transcription factors has been well characterized in leukemogenesis and regarded as an ideal target in antileukemia strategies, the effect of RUNX-inhibition therapy on bone marrow niche cells andr its impact on the engraftment of acute myeloid leukemia (AML) cells have largely been unknown. Here, we provide evidence suggesting the possible involvement of RUNX transcription factors in the transactivation of E-selectin, a member of selectin family of cell adhesion molecules, on the vascular endothelial cells of the mice bone marrow niche. In our experiments, gene switch-mediated silencing of RUNX downregulated E-selectin expression in the vascular niche and negatively controlled the engraftment of AML cells in the bone marrow, extending the overall survival of leukemic mice. Our work identified the novel role of RUNX family genes in the vascular niche and showed that the vascular niche, a home for AML cells, could be strategically targeted with RUNX-silencing antileukemia therapies. Considering the excellent efficacy of RUNX-inhibition therapy on AML cells themselves as we have previously reported, this strategy potentially targets AML cells both directly and indirectly, thus providing a better chance of cure for poor-prognostic AML patients.


Assuntos
Vasos Sanguíneos/metabolismo , Medula Óssea/irrigação sanguínea , Subunidades alfa de Fatores de Ligação ao Core/fisiologia , Selectina E/genética , Animais , Subunidades alfa de Fatores de Ligação ao Core/genética , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Inativação Gênica , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Fatores de Transcrição/fisiologia
16.
Sci Rep ; 7(1): 16604, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29192243

RESUMO

Although runt-related transcription factor 1 (RUNX1) and its associating core binding factor-ß (CBFB) play pivotal roles in leukemogenesis, and inhibition of RUNX1 has now been widely recognized as a novel strategy for anti-leukemic therapies, it has been elusive how leukemic cells could acquire the serious resistance against RUNX1-inhibition therapies and also whether CBFB could participate in this process. Here, we show evidence that p53 (TP53) and CBFB are sequentially up-regulated in response to RUNX1 depletion, and their mutual interaction causes the physiological resistance against chemotherapy for acute myeloid leukemia (AML) cells. Mechanistically, p53 induced by RUNX1 gene silencing directly binds to CBFB promoter and stimulates its transcription as well as its translation, which in turn acts as a platform for the stabilization of RUNX1, thereby creating a compensative RUNX1-p53-CBFB feedback loop. Indeed, AML cells derived from relapsed cases exhibited higher CBFB expression levels compared to those from primary AML cells at diagnosis, and these CBFB expressions were positively correlated to those of p53. Our present results underscore the importance of RUNX1-p53-CBFB regulatory loop in the development and/or maintenance of AML cells, which could be targeted at any sides of this triangle in strategizing anti-leukemia therapies.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade beta de Fator de Ligação ao Core/metabolismo , Leucemia Mieloide Aguda/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Modelos Biológicos , RNA Interferente Pequeno/genética , Transcrição Gênica , Proteína Supressora de Tumor p53/genética
17.
Eur J Med Chem ; 138: 320-327, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28686912

RESUMO

In parallel to monomeric epigenetic regulators, sequence-specific epigenetic regulators represent versatile synthetic dual-target ligands that achieve regulatory control over multi-gene networks. Development of DNA-binding domain (DBD)-HDAC inhibitors and DBD-HAT activators, which result in increased histone acetylation, has become one promising research field. However, there is no report regarding the gene regulatory pattern by sequence-specific epigenetic repressor. We report here for the first time, the synthesis of DBD-HAT inhibitors and demonstrate that these conjugates could retain their dual-target activity using predicted working model of thermal stability assay and in vitro HAT activity assay. Evaluation of antiproliferative activity in cancer cells showed that 2 (with a medium linker length of 13-atom) exhibited the highest antiproliferative activity in p53 wild-type cancer cell lines (IC50 of 1.8-2.6 µM in A549 and MV4-11 cells) and not in p53 mutant cancer cell lines. A mechanistic investigation using microarray analysis and an apoptotic assay showed that the antiproliferative effect of 2 occurred via the up-regulation of p53 target genes, and the subsequent initiation of p53-dependent apoptosis. Our research on sequence-specific dual-target epigenetic repressor offers us an alternative way to modulate HAT-governed therapeutically important genes and contributes to offer a fresh insight into antitumor therapeutics.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Histona Acetiltransferases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Oximas/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular , Oximas/química , Pirróis/química , Relação Estrutura-Atividade
18.
J Clin Invest ; 127(7): 2815-2828, 2017 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-28530640

RESUMO

Runt-related transcription factor 1 (RUNX1) is generally considered to function as a tumor suppressor in the development of leukemia, but a growing body of evidence suggests that it has pro-oncogenic properties in acute myeloid leukemia (AML). Here we have demonstrated that the antileukemic effect mediated by RUNX1 depletion is highly dependent on a functional p53-mediated cell death pathway. Increased expression of other RUNX family members, including RUNX2 and RUNX3, compensated for the antitumor effect elicited by RUNX1 silencing, and simultaneous attenuation of all RUNX family members as a cluster led to a much stronger antitumor effect relative to suppression of individual RUNX members. Switching off the RUNX cluster using alkylating agent-conjugated pyrrole-imidazole (PI) polyamides, which were designed to specifically bind to consensus RUNX-binding sequences, was highly effective against AML cells and against several poor-prognosis solid tumors in a xenograft mouse model of AML without notable adverse events. Taken together, these results identify a crucial role for the RUNX cluster in the maintenance and progression of cancer cells and suggest that modulation of the RUNX cluster using the PI polyamide gene-switch technology is a potential strategy to control malignancies.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Subunidades alfa de Fatores de Ligação ao Core , Leucemia Mieloide Aguda , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos Alquilantes/química , Linhagem Celular Tumoral , Subunidades alfa de Fatores de Ligação ao Core/genética , Subunidades alfa de Fatores de Ligação ao Core/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Nylons/química , Nylons/farmacologia , Pirróis/química , Pirróis/farmacologia , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Blood Adv ; 1(18): 1440-1451, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-29296785

RESUMO

Besides being a classical tumor suppressor, runt-related transcription factor 1 (RUNX1) is now widely recognized for its oncogenic role in the development of acute myeloid leukemia (AML). Here we report that this bidirectional function of RUNX1 possibly arises from the total level of RUNX family expressions. Indeed, analysis of clinical data revealed that intermediate-level gene expression of RUNX1 marked the poorest-prognostic cohort in relation to AML patients with high- or low-level RUNX1 expressions. Through a series of RUNX1 knockdown experiments with various RUNX1 attenuation potentials, we found that moderate attenuation of RUNX1 contributed to the enhanced propagation of AML cells through accelerated cell-cycle progression, whereas profound RUNX1 depletion led to cell-cycle arrest and apoptosis. In these RUNX1-silenced tumors, amounts of compensative upregulation of RUNX2 and RUNX3 expressions were roughly equivalent and created an absolute elevation of total RUNX (RUNX1 + RUNX2 + RUNX3) expression levels in RUNX1 moderately attenuated AML cells. This elevation resulted in enhanced transactivation of glutathione S-transferase α 2 (GSTA2) expression, a vital enzyme handling the catabolization of intracellular reactive oxygen species (ROS) as well as advancing the cell-cycle progressions, and thus ultimately led to the acquisition of proliferative advantage in RUNX1 moderately attenuated AML cells. Besides, treatment with ethacrynic acid, which is known for its GSTA inhibiting property, actually prolonged the survival of AML mice in vivo. Collectively, our findings indicate that moderately attenuated RUNX1 expressions paradoxically enhance leukemogenesis in AML cells through intracellular environmental change via GSTA2, which could be a novel therapeutic target in antileukemia strategy.

20.
Acute Med Surg ; 2(2): 138-142, 2015 04.
Artigo em Inglês | MEDLINE | ID: mdl-29123710

RESUMO

Aim: We compared the utility of the conventional Macintosh laryngoscope, the Pentax Airway Scope, and the McGrath MAC video laryngoscope under restricted cervical motion using a manikin. Methods: We recruited 36 participants into the simulation study. The manikin's cervical motion was restricted with a cervical collar and a head immobilizer, as occurs in trauma cases. We recorded the time to intubation and the success rate of the intubations. Results: Data are medians and ranges. The time to intubation under normal and restricted cervical motion were 22.5 (10-78) and 23 (9-119) s with the Macintosh laryngoscope, 13.5 (5-50) and 14 (7-119) s with the Airway Scope, and 13 (6-32) and 18 (7-80) s with the McGrath MAC video laryngoscope. The differences in the time to intubation between normal and restricted cervical motion were significant only with the McGrath MAC (P = 0.0008). With restricted cervical motion, the times to intubation in the Airway Scope attempts were significantly shorter than those in the Macintosh laryngoscope (P = 0.0005) and McGrath MAC (P = 0.0282) attempts. The success rates under normal and restricted cervical motion were 100% and 80.6% with the Macintosh laryngoscope (P = 0.0054), 100% and 100% with the Airway Scope, and 100% and 97.2% with the McGrath MAC, respectively. Conclusion: In the present study, the Airway Scope was the best among the three devices. However, the differences between the Airway Scope and the McGrath MAC video laryngoscope may not be serious in a clinical situation. Data were gathered using a manikin, and further studies will be necessary.

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