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BACKGROUND: The utilization of biomarkers has become increasingly active to enhance efficiency of clinical development. This study evaluated the current situation and quantitative impact of co-development of companion diagnostics (CDx) on the oncology drug development in Japan. METHODS: Based on publicly available information about the oncology drugs and CDx approved in Japan in 2010-2020, we evaluated the approval lag time between drugs and CDx, and the duration between the pivotal study start date and the new drug application submission date (the time to application). Influences of multiple factors including the use of CDx on the time to application were also analyzed. RESULTS: A diagnostic test was mostly used from an early development phase such as phase1/2 study, and the median approval lag has tended to decrease when approved CDx were used (- 507 vs. - 25 days for newly developed CDx). The shorter median times to application were observed in Drugs with CDx (1204 days) compared to Targeted therapies without CDx (1423 days) or Other drugs without CDx (1853 days), although both the cancer types and the implementation of multi-regional clinical trials have a larger impact on the time to application compared to the use of CDx. CONCLUSIONS: The use of CDx from the early development phase and the global development strategy could have a positive contribution on the development period of oncology drugs, which will facilitate patients' earlier access to the optimal treatment.
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Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Biomarcadores , Desenvolvimento de Medicamentos , Humanos , Japão , Neoplasias/tratamento farmacológicoRESUMO
Coronin-1, a hematopoietic cell-specific actin-binding protein, is thought to be involved in the phagocytic process through its interaction with actin filaments. The dissociation of coronin-1 from phagosomes after its transient accumulation on the phagosome surface is associated with lysosomal fusion. We previously reported that 1) coronin-1 is phosphorylated by protein kinase C (PKC), 2) coronin-1 has two phosphorylation sites, Ser-2 and Thr-412, and 3) Thr-412 of coronin-1 is phosphorylated during phagocytosis. In this study, we examined which PKC isoform is responsible for the phosphorylation of coronin-1 at Thr-412 by using isotype-specific PKC inhibitors and small interfering RNAs (siRNAs). Thr-412 phosphorylation of coronin-1 was suppressed by Gö6976, an inhibitor of PKCα and PKCßI. This phosphorylation was attenuated by siRNA for PKCα, but not by siRNA for PKCß. Furthermore, Thr-412 of coronin-1 was phosphorylated by recombinant PKCα in vitro, but not by recombinant PKCß. We next examined the effects of Gö6976 on the intracellular distribution of coronin-1 in HL60 cells during phagocytosis. The confocal fluorescence microscopic observation showed that coronin-1 was not dissociated from phagosomes in Gö6976-treated cells. These results indicate that phosphorylation of coronin-1 at Thr-412 by PKCα regulates intracellular distribution during phagocytosis.
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BACKGROUND: It is considered important that the applicants and reviewers communicate well from the development stage and that both mutually understand the development strategy and application contents in conducting the review efficiently after the application is submitted. Therefore, we focus on Pharmaceuticals and Medical Devices Agency (PMDA) consultations from the viewpoint of communication before the application and clarify the issues to consider in the challenge to reduce the review time in terms of the relationship between the review time and various PMDA consultations. METHODS: We investigated the relationship between the review time and various PMDA consultations for the drugs with new active ingredients approved in Japan using public information from the PMDA. RESULTS: Review times tended to be shorter as more PMDA consultations were conducted. In standard review products, statistically significant differences were noted in the review times (median). When looking at the results of the cases of each category of PMDA consultations, variations in the review times were greater as the consultations were conducted in the later stages of clinical development. Review times tended to be shorter when prior assessment consultations were conducted. In standard review products, significant reductions were noted with the review time (median). CONCLUSIONS: It was suggested that conducting more PMDA consultations might lead to shorter review times. Regarding the review times, variations from the standard review time could possibly be smaller by conducting PMDA consultations from the early stage of clinical development in Japan. It was suggested that review times could possibly be further reduced by conducting prior assessment consultations.
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Aprovação de Drogas/organização & administração , Indústria Farmacêutica/organização & administração , Comunicação , Órgãos Governamentais , Humanos , Japão , Encaminhamento e Consulta , Fatores de TempoRESUMO
PURPOSE: The objective of this study is to specify the most reported adverse events as preferred terms (PTs) and to compare the reported adverse events about some properties including the number of report and time-to-onset (TTO) distribution of the originator of filgrastim Neupogen® and its biosimilars in Europe, using VigiBase®. METHODS: We identified the biosimilar which was reported as the suspected drug in more than 100 individual case safety reports in Europe. Then, we specified the top ranking 10 PTs in the cases reported with Neupogen® or each biosimilar as the suspected drug. We also compared the TTO of the most reported PTs using the data about the onset date of the PT and the start date of filgrastim. We used Kolmogorov-Smirnov method to detect significant difference. RESULTS: The total ICSR numbers with Neupogen® and 3 biosimilars, Zarzio®, Nivestim®, and Tevagrastim® were 1,301, 295, 156, and 127, respectively, in Europe. The most reported PTs with Neupogen® were bone pain, pyrexia, and dyspnoea. The TTO of bone pain and pyrexia with Zarzio® (N: 22 and 16, median: 1 and 0.5 days) were significantly shorter than those with Neupogen® (P < 0.01, N: 72 and 33, median: 3.5 and 3 days), respectively. The most reported PTs with biosimilars were drug ineffective and neutropenia. CONCLUSION: The difference in the TTO was identified between originator filgrastim Neupogen and its biosimilar regarding some PTs, which may suggest the difference in their safety profile. Copyright © 2017 John Wiley & Sons, Ltd.
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Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Medicamentos Biossimilares/efeitos adversos , Interpretação Estatística de Dados , Filgrastim/efeitos adversos , Fármacos Hematológicos/efeitos adversos , Sistemas de Notificação de Reações Adversas a Medicamentos/tendências , Seguimentos , Humanos , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Dor/induzido quimicamente , Dor/epidemiologia , Fatores de TempoRESUMO
OBJECTIVE: The aim of this study was to investigate the correlation between human epidermal growth factor receptor 2 (HER2)-related biomarkers and the treatment outcomes using lapatinib plus capecitabine (LC) and to evaluate the influence of the estrogen receptor (ER) status in trastuzumab-refractory HER2-positive advanced breast cancer. METHOD: Eighty patients were enrolled in this study. Total HER2, p95HER2, and total HER3 expression were quantified using the VeraTag assays. PTEN (phosphatase and tensin homolog) and p95 expression was evaluated using immunohistochemistry and PIK3CA mutation using direct sequencing. RESULTS: The response rate to LC was 30%, clinical benefit rate was 51.3%, and the median progression-free survival (PFS) was 174.5 days. ER negativity significantly correlated with higher HER2 and p95HER2. The lower HER2 and PIK3CA mutations were often observed in the nonresponders. A high p95HER2 expression correlated with longer PFS especially in the high HER2- and ER-positive cases. Patients without the PIK3CA mutation showed longer PFS in the same subset. Overall survival after LC significantly correlated with the number of recurrence organs. CONCLUSION: LC therapy is effective in trastuzumab-refractory HER2-positive breast cancer. Moreover, the biomarker expression differed depending on ER status, and a high p95HER2 expression and wild-type PIK3CA gene correlated with longer PFS especially in the ER-positive cases.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Capecitabina/uso terapêutico , Quinazolinas/uso terapêutico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Capecitabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , PTEN Fosfo-Hidrolase/efeitos dos fármacos , Quinazolinas/administração & dosagem , Trastuzumab/administração & dosagem , Resultado do Tratamento , Adulto JovemRESUMO
Perivascular epithelial cell tumors (PEComas), firstly described by Bonetti in 1992, are a family of mesenchymal tumor composed of perivascular epithelioid cells having epithelioid or spindle morphology and exhibiting melanocytic and myogenic immunoreactivities. We herein described a 61-year-old woman who presented with epigastric pain. Preoperative imaging studies showed that 7-cm-sized mass was located in pancreatic head and body, and pancreaticoduodenectomy was performed. Histological findings showed that the tumor was composed of clear epithelioid cells with abundant glycogen granules, which grew in a nested and alveolar pattern around blood vessels. The tumor cells showed immunoreactivities for HMB-45 but did not express epithelial or endocrine markers. These histological features indicated those of PEComa. This report underlines that we should recognize PEComa as a preoperative differential diagnosis of pancreatic tumors.
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BACKGROUND: A significant number of inquiries are issued during the review of pharmaceutical products developed using the quality-by-design (QbD) approach in Japan. The purpose of this article was to identify key elements specific to QbD development that should be described in the Quality Overall Summary (QOS) dossier. METHODS: The review reports of the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) were investigated to identify review points for QbD products. Based on the results, key considerations for preparing the QOS of QbD products were determined. RESULTS: The primary review points for QbD products were control strategy (â¼30%), design space (â¼15%), and real-time release (â¼15%). Additionally, the market authorization application form (AF) was discussed more frequently for QbD products than for products developed using a traditional approach. Based on the results, a "QOS checklist for QbD products" was developed to highlight key elements of QbD products that should be included in the QOS. CONCLUSIONS: It is important to explain the scientific rationale for the control strategy, design space, and real-time release in the QOS and how "regulatory flexibility" is expressed in the AF. The QOS checklist enables applicants to prepare an appropriately detailed QOS that should satisfy the PMDA's critical review points. The following are recommended for further discussion topics to enable efficient and consistent review by the PMDA for QbD products: (1) Clear guidance on how to express "regulatory flexibility" in the AF and (2) a "QOS checklist for QbD products" that is agreed upon by both regulatory agencies and pharmaceutical companies.
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PURPOSE: The aim of this study was to investigate the validity of the management strategy for intraductal papillary mucinous neoplasms (IPMNs) advocated by the international consensus guidelines 2012 (ICG2012). METHODS: The medical records of 49 patients who underwent pancreatectomy for IPMN were retrospectively reviewed. RESULTS: According to preoperative imaging, 10 patients (20 %) had main-duct IPMNs, 20 (41 %) had mixed IPMNs, and 19 (39 %) had branch-duct IPMNs, with malignancy frequencies of 80, 15, and 37 %, respectively. Twenty-seven patients had high-risk stigmata and 21 had worrisome features, with malignancy frequencies of 59 and 10 %, respectively. The sensitivity, specificity, and positive and negative predictive values of high-risk stigmata for malignancy were 88, 65, 59, and 91 %, respectively. Lesions were malignant in 88 % of patients with an enhanced solid component, which was significantly correlated with the prevalence of malignancy (P < 0.01). However, of the 10 patients who underwent pancreatectomy solely due to a main pancreatic dilation of ≥10 mm, 9 (90 %) had benign IPMNs. CONCLUSIONS: Many mixed IPMNs defined according to ICG2012 are benign. Although the management strategy advocated by ICG2012 has been improved relative to the Sendai criteria, the different high-risk stigmata carry unequal weights. Consequently, ICG2012 remains suboptimal for predicting malignant IPMN.
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Adenocarcinoma Mucinoso/cirurgia , Carcinoma Ductal Pancreático/cirurgia , Neoplasias Pancreáticas/cirurgia , Guias de Prática Clínica como Assunto , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/diagnóstico por imagem , Diagnóstico por Imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatectomia , Neoplasias Pancreáticas/diagnóstico por imagem , Estudos Retrospectivos , RiscoRESUMO
This study examined the pathological complete response (pCR )rate and safety of induction chemotherapy with 12 cycles of weekly paclitaxel (80 mg/m²) followed by 4 cycles of 5-fluorouracil (500 mg/m²), epirubicin (100 mg/m²), and cyclo- phosphamide (500 mg/m²). The study medication was administered to female patients (n=31)with a mean age of 51 years, diagnosed with stage II A (n=18), II B (n=11) and III A (n=2) disease and with an estrogen receptor positive rate of 65% (20/31). No patient was HER2-IHC [human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC)](3+) or HER2-FISH (fluorescence in situ hybridization) positive. Twenty-eight patients completed the treatment regimen. Treatment was halted in 2/31 patients due to progression of disease in one patient and a Grade 3 non-hematological adverse effect of skin eruption and itching in the other patient. A third patient died of causes unrelated to the study medication. Central review ascertained a pCR in 6 patients. In patients with triple-negative disease we observed a pCR rate of 67% (6/9). In patients with the Luminal (A+B) subtype, 0% (0/19) had a pCR. Grade 3/4 toxicity included leucopenia (58%), neutropenia (58%), febrile neutropenia (26%), fatigue (10%), and ALT elevation (7%). In terms of pCR, patients presenting with triple-negative disease and manageable safety profiles appear to respond well to this treatment regimen, while only a modest response was observed in patients with Luminal subtype disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Ciclofosfamida/administração & dosagem , Epirubicina/administração & dosagem , Fluoruracila/administração & dosagem , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagemRESUMO
We herein report an extremely rare case of ductal carcinoma in situ (DCIS) arising in tubular adenoma of the breast. A 33-year-old female first noticed a mass in her right breast when she was 15 years old. The tumor had not changed in size subjectively for 18 years. She finally visited the hospital one and a half years before this presentation for an examination of her breast mass. Ultrasonography (US) showed a circumscribed mass suggesting a benign tumor, and mammography (MMG) revealed the well-defined high-density mass with a focal region of microcalcification. It was suspected to be adenosis based on a core-needle biopsy (CNB). During the regular follow-up, the microcalcification in the mass increased. She was therefore referred to our hospital for further examination. US and MMG showed a well-demarcated mass with a focal microcalcified area. US-guided CNB diagnosed it as DCIS with tubular adenoma. The patient underwent tumorectomy. Histologically, the tumor was diagnosed to be DCIS in tubular adenoma with negative surgical margins.
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Adenoma/patologia , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Adolescente , Adulto , Biópsia com Agulha de Grande Calibre , Neoplasias da Mama/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Feminino , Humanos , UltrassonografiaRESUMO
Immunoglobulin G4-related disease, a newly emerging systemic autoimmune disorder, can potentially involve the cardiovascular system. The standard treatment for immunoglobulin G4-related cardiovascular disease has not been established. We encountered a very rare case of an immunoglobulin G4-related inflammatory abdominal aortic aneurysm coexisting with a coronary artery aneurysm and periarteritis. The patient underwent surgical resection for the abdominal aortic aneurysm, followed by successful corticosteroid therapy for the coronary artery lesions. This is the first report of steroid-sensitive immunoglobulin G4-related coronary artery disease. A carefully planned treatment strategy for the multiple cardiovascular lesions was invaluable in the present case.
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Corticosteroides/uso terapêutico , Aneurisma da Aorta Abdominal/cirurgia , Doenças Autoimunes/tratamento farmacológico , Implante de Prótese Vascular , Aneurisma Coronário/tratamento farmacológico , Imunoglobulina G/sangue , Imunossupressores/uso terapêutico , Idoso , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/diagnóstico , Aneurisma da Aorta Abdominal/imunologia , Aortografia/métodos , Arterite/diagnóstico , Arterite/tratamento farmacológico , Arterite/imunologia , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Biomarcadores/sangue , Biópsia , Terapia Combinada , Aneurisma Coronário/sangue , Aneurisma Coronário/diagnóstico , Aneurisma Coronário/imunologia , Humanos , Imuno-Histoquímica , Masculino , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Catamenial pneumothorax (CP) is a rare entity of spontaneous, recurring pneumothorax in females. Although it has been known to be associated with thoracic endometriosis, varying clinical course and the lack of consistent intraoperative findings have led to conflicting etiological theories. We herein discuss the etiology, clinical course, and surgical treatment of three patients with CP. Three females (aged 40 years, 28 years, and 34 years) had recurrent right-sided spontaneous pneumothoraces that coincided with their menses. They had undergone video-assisted thoracoscopic surgery (VATS) previously. Blueberry spots in the right diaphragm were detected in all three cases. Two patients had recurrence, postoperatively. The other patient, who received luteinizing hormone-releasing hormone analog therapy for an abdominal endometriosis in the perioperative period and postoperative chemical pleurodesis to prevent recurrence, has been free of recurrence for 15 months, postoperatively. However, pelvic endometriosis was detected in this patient only. Therefore, CP should be suspected in ovulating females with spontaneous pneumothorax, even in the absence of any symptoms associated with pelvic endometriosis. In addition, while performing VATS, careful inspection of the diaphragmatic surface is important. In complicated cases, hormonal suppression therapy and chemical pleurodesis might also be helpful adjunct modalities.
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Pneumotórax/cirurgia , Cirurgia Torácica Vídeoassistida , Adulto , Feminino , Humanos , Menstruação , Pneumotórax/diagnóstico , Pneumotórax/etiologia , RecidivaAssuntos
Neoplasias Pulmonares/congênito , Neoplasias Pulmonares/patologia , Neoplasias de Tecido Muscular/congênito , Neoplasias de Tecido Muscular/patologia , Adulto , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Neoplasias Pulmonares/diagnóstico , Masculino , Neoplasias de Tecido Muscular/diagnóstico , Parto/fisiologiaRESUMO
To evaluate the diagnostic yield of the procedure, mucosal-incision assisted biopsy (MIAB), for the histological diagnosis of gastric gastrointestinal stromal tumor (GIST), we performed a retrospective review of the 27 patients with suspected gastric GIST who underwent MIAB in our hospitals. Tissue samples obtained by MIAB were sufficient to make a histological diagnosis (diagnostic MIAB) in 23 out of the 27 patients, where the lesions had intraluminal growth patterns. Alternatively, the samples were insufficient (non-diagnostic MIAB) in remaining 4 patients, three of whom had gastric submucosal tumor with extraluminal growth patterns. Although endoscopic ultrasound and fine needle aspiration is the gold standard for obtaining tissue specimens for histological and cytological analysis of suspected gastric GISTs, MIAB can be used as an alternative method for obtaining biopsy specimens of lesions with an intraluminal growth pattern.
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INTRODUCTION: Endoscopic surgery is reportedly associated with smaller scars and greater patient satisfaction. Herein we evaluate the early results of endoscopy-assisted breast-conserving surgery(E-BCS). METHODS: Between May 2009 and October 2010, 61 women with breast cancer underwent E-BCS. We performed E-BCS on patients with tumors measuring less than 2 cm, without skin or pectoralis muscles invasion. Any patients with microcalcified lesions or axillary lymph node metastasis were excluded. We used an endoscopic vein retractor to dissect the dorsal layer of the mammary gland from a small axillar incision. We dissected the subcutaneous layer and cut the mammary gland vertically from a periareolar incision. We evaluated the clinicopathological characteristics, the surgical outcomes, and early cosmetic results. RESULTS: The mean age of the patients was 58.5 years, and the mean tumor size was 1.4 cm. Sentinel node biopsy was positive in seven patients, all of whom underwent axillary node dissection. An additional intraoperative resection of the breast was performed in 12 patients. The mean length of the operation was 167 min, and the mean blood loss was 27 mL. Eight patients received a boost to the tumor bed. The cosmetic results were satisfactory, and the wound scar was inconspicuous in most patients. CONCLUSION: Herein we demonstrate that E-BCS is a feasible and safe procedure for patients with early breast cancer. It allows for a better cosmetic scar location and offers patients favorable aesthetic results in the short-term follow-up results.
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Adenocarcinoma/cirurgia , Neoplasias da Mama/cirurgia , Cicatriz/prevenção & controle , Endoscopia , Mastectomia Segmentar/métodos , Adenocarcinoma/patologia , Adulto , Idoso , Neoplasias da Mama/patologia , Cicatriz/etiologia , Cicatriz/patologia , Estudos de Coortes , Feminino , Humanos , Mastectomia Segmentar/efeitos adversos , Pessoa de Meia-Idade , Duração da Cirurgia , Satisfação do Paciente , Resultado do TratamentoRESUMO
Trastuzumab (T) has contributed to improving the prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Although some patients have been unresponsive or resistant to T. Loss of phosphatase and tensin homolog (PTEN) deleted on chromosome 10, PIK3CA mutation and p95HER2 expression have been reported to potentially be responsible for the poor response to T. This is a small-scale pilot study to be followed by a large-scale investigation examining the association between the biomarkers and clinical response. Based on the response to T, patients were divided into 3 groups in terms of progression-free survival (PFS): PFS >8 months (group A, n=15), 3-8 months (group B, n=7) and PFS <3 months (group C, n=11). PTEN protein expression was detected by immunohistochemistry and PIK3CA mutation by direct sequencing. The median age was 61, 60 and 47 years in groups A, B and C, respectively, with statistically significant differences among the groups. No additional patient background factors differed between the groups. A decreased PTEN expression (H score, <100) was observed in 33.3 and 72.7% of patients in groups A and C, respectively. PTEN loss was slightly correlated with poor response to T. PIK3CA mutation frequency in exons 9/20 was 33.3% in group A and 27.3% in group C, with no significant correlation between PIK3CA mutation and clinical response. In this small-scale pilot study, a weak correlation was demonstrated between PTEN loss and poor response to T. This potential correlation is likely to be confirmed in the planned large-scale study, while the association of PIK3CA mutation and p95HER2 expression with poor response to T also requires examination.
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The actin-binding protein p57/coronin-1, a member of the coronin protein family, is selectively expressed in hematopoietic cells and plays crucial roles in the immune response through reorganization of the actin cytoskeleton. We previously reported that p57/coronin-1 is phosphorylated by protein kinase C, and the phosphorylation down-regulates the association of this protein with actin. In this study we analyzed the phosphorylation sites of p57/coronin-1 derived from HL60 human leukemic cells by MALDI-TOF-MS, two-dimensional gel electrophoresis, and Phos-tag® acrylamide gel electrophoresis in combination with site-directed mutagenesis and identified Ser-2 and Thr-412 as major phosphorylation sites. A major part of p57/coronin-1 was found as an unphosphorylated form in HL60 cells, but phosphorylation at Thr-412 of p57/coronin-1 was detected after the cells were treated with calyculin A, a Ser/Thr phosphatase inhibitor, suggesting that p57/coronin-1 undergoes constitutive turnover of phosphorylation/dephosphorylation at Thr-412. A diphosphorylated form of p57/coronin-1 was detected after the cells were treated with phorbol 12-myristate 13-acetate plus calyculin A. We then assessed the effects of phosphorylation at Thr-412 on the association of p57/coronin-1 with actin. A co-immunoprecipitation experiment with anti-p57/coronin-1 antibodies and HL60 cell lysates revealed that ß-actin was co-precipitated with the unphosphorylated form but not with the phosphorylated form at Thr-412 of p57/coronin-1. Furthermore, the phosphorylation mimic (T412D) of p57/coronin-1 expressed in HEK293T cells exhibited lower affinity for actin than the wild-type or the unphosphorylation mimic (T412A) did. These results indicate that the constitutive turnover of phosphorylation at Thr-412 of p57/coronin-1 regulates its interaction with actin.
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Actinas/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosfotreonina/metabolismo , Sequência de Aminoácidos , Benzofenantridinas/farmacologia , Eletroforese em Gel Bidimensional , Células HEK293 , Células HL-60 , Humanos , Proteínas dos Microfilamentos/química , Dados de Sequência Molecular , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Fagocitose/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Serina/metabolismoRESUMO
We evaluated the efficacy and safety of the epirubicin plus docetaxel(ET)regimen, which is a combination of active agents given to patients with inflammatory breast cancer(IBC)as a primary therapy. Nineteen patients received ET(60, 60mg/m2) every 3 weeks for 4 courses, and appropriate surgery was offered unless disease progression occurred. Seventeen patients completed the ET regimen and 1 patient was excluded because of no diffuse erythema, leaving 18 patients evaluable for the response and safety profile of this regimen. Grade 3/4 hematological toxicities were neutropenia in 15 patients(79%), febrile neutropenia in 8 patients(42%)and anemia in 3 patients(16%). Six patients(63%)received granulocyte colony-stimulating factor for febrile neutropenia. Febrile neutropenia was observed only for 1 course in all 6 patients and progression to apparent infection was not observed. Grade 3/4 non-hematological toxicities were constipation in 3, nausea in 2, anorexia in 2, fatigue in 1, vomiting in 1, diarrhea in 1, and stomatitis in 1 patient. The ET regimen was given to 16 patients(89%)as planned. The median number of courses was 4(range: 2-4). The clinical response rate was 44%. The median time to progression was 9 months, and median overall survival was 26 months. It is concluded that the ET regimen was well tolerated and effective as a primary chemotherapy for IBC.