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- Inhibition of DNA topoisomerase II selectively reduces the threat of tumorigenicity following induced pluripotent stem cell-based myocardial therapy. [JOURNAL ARTICLE]
- Stem Cells Dev 2014 Jul 18.
The advent of induced pluripotent stem cell (iPSC) technology creates new opportunities for transplant-based therapeutic strategies. The potential for clinical translation is currently hindered by the risk of dysregulated cell growth. Pluripotent stem cells reprogrammed by three-factor (Sox2, Klf, Oct4) and four-factor (Sox2, Klf, Oct4, c-Myc) strategies results in the capacity for teratogenic growth from residual pluripotent progeny upon in vivo transplantation. However, these pluripotent stem cells also have a stage-specific hypersensitivity to DNA damaging agents that may allow separation of lineage-specific therapeutic subpopulation of cells. We aimed to demonstrate the selective effect of DNA topoisomerase II inhibitor, etoposide, in eliminating pluripotent cells in the early cardiac progenitor population thus decreasing the effect of teratoma formation. Immunodeficient murine hearts were infarcted and received implantation of a therapeutic dose of cardiac progenitors derived from partially differentiated iPSCs. Etoposide-treated cell implantation reduced mass formation in the intra-cardiac and extra-cardiac/chest cavity compared to the same dose of iPSC-derived cardiac progenitors in the control untreated group. In vivo bioluminescence imaging confirmed the localization and engraftment of transplanted cells in the myocardium post-injection in both groups. Comparatively, the equivalent cell population without etoposide treatment demonstrated a greater incidence and size of teratoma formation. Hence, pretreatment with genotoxic etoposide significantly lowered the threat of teratogenicity by purging the contaminating pluripotent cells, establishing an adjunctive therapy to further harness the clinical-value of iPSC-derived cardiac regeneration.
- Synchronous primary cancers of trachea and esophagus and ventricular tachycardia. [Journal Article]
- Chin J Cancer Res 2014 Jun; 26(3):345-50.
The incidence of multiple primary cancers involving trachea is rare. We present a case of synchronous double primary cancer of trachea and esophagus in a 70-year-old woman, with a special symptom of ventricular tachycardia and no history of smoking and alcohol drinking. Biopsies from multiple foci demonstrated the patient had primary small cell cancer of trachea and squamous cell carcinoma in situ of esophagus. The patient was successfully treated with four cycles of chemotherapy consisting of etoposide and carboplatin (EC) followed by thoracic radiotherapy (60 Gy in 30 fractions, in 6 weeks), and was evaluated to have complete response of tumor. To our knowledge, there is no synchronous cancer of trachea and esophagus has been reported in English literature, and our experience showed sequential EC chemotherapy and radiotherapy provided an effective treatment to control both cancers.
- Evaluation of inhibitory effects of benzothiazole and 3-amino-benzothiazolium derivatives on DNA topoisomerase II by molecular modeling studies. [JOURNAL ARTICLE]
- SAR QSAR Environ Res 2014 Jul 16.:1-13.
There has been considerable interest in DNA topoisomerases over the last decade, as they have been shown to be one of the major cellular targets in anticancer drug development. Previously we synthesized some benzothiazole derivatives and corresponding benzothiazolium forms, and tested their DNA inhibitory activity to develop novel antitumor agents. Among the 12 prepared compounds, compound BM3 (3-aminobenzothiazole-3-ium 4-methylbenzene sulfonate) exhibited extreme topoisomerase II inhibitory activity compared with the reference drug etoposide. We also tried to determine the DNA and enzyme binding abilities of BM3 and found that BM3 acted on topoisomerase II first at low doses, while it had also showed DNA minor groove binding properties at higher doses. In this study the interactions between DNA topoisomerase II and the compounds were examined in detail by molecular modelling studies such as molecular docking and pharmacophore analysis performed using Discovery Studio 3.5. As a result, it was found that benzothiazolium compounds exhibited a totally different mechanism than benzothiazoles by binding to the different amino acids at the active site of the protein molecule. 3-Aminobenzothiazoliums are worthy of carrying onto anticancer studies; BM3 especially would be a good anticancer candidate for preclinical studies.
- Targeting Cancer Stem Cell Plasticity Through Modulation of Epidermal Growth Factor and Insulin-Like Growth Factor Receptor Signaling in Head and Neck Squamous Cell Cancer. [JOURNAL ARTICLE]
- Stem Cells Transl Med 2014 Jul 14.
Emerging data suggest that cancer stem cells (CSCs) exist in equilibrium with differentiated cells and that stochastic transitions between these states can account for tumor heterogeneity and drug resistance. The aim of this study was to establish an in vitro system that recapitulates stem cell plasticity in head and neck squamous cell cancers (HNSCCs) and identify the factors that play a role in the maintenance and repopulation of CSCs. Tumor spheres were established using patient-derived cell lines via anchorage-independent cell culture techniques. These tumor spheres were found to have higher aldehyde dehydrogenase (ALD) cell fractions and increased expression of Kruppel-like factor 4, SRY (sex determining region Y)-box 2, and Nanog and were resistant to γ-radiation, 5-fluorouracil, cisplatin, and etoposide treatment compared with monolayer culture cells. Monolayer cultures were subject to single cell cloning to generate clones with high and low ALD fractions. ALD(High) clones showed higher expression of stem cell and epithelial-mesenchymal transition markers compared with ALD(Low) clones. ALD fractions, representing stem cell fractions, fluctuated with serial passaging, equilibrating at a level specific to each cell line, and could be augmented by the addition of epidermal growth factor (EGF) and/or insulin. ALD(High) clones showed increased EGF receptor (EGFR) and insulin-like growth factor-1 receptor (IGF-1R) phosphorylation, with increased activation of downstream pathways compared with ALD(Low) clones. Importantly, blocking these pathways using specific inhibitors against EGFR and IGF-1R reduced stem cell fractions drastically. Taken together, these results show that HNSCC CSCs exhibit plasticity, with the maintenance of the stem cell fraction dependent on the EGFR and IGF-1R pathways and potentially amenable to targeted therapeutics.
- A prospective study of mediastinal gray zone lymphoma. [JOURNAL ARTICLE]
- Blood 2014 Jul 14.
Mediastinal B-cell lymphomas present in the mediastinum and are most frequent in young patients. Nodular sclerosis Hodgkin lymphoma (NSHL) and primary mediastinal B-cell lymphoma (PMBL) are the common types, whereas mediastinal gray zone lymphoma (MGZL) is extremely rare and has pathological features intermediate between NSHL and PMBL. The indeterminate pathobiology of MGZL has led to uncertainty regarding therapeutic strategy, and its clinical characteristics and treatment have not been characterized. We conducted a prospective study of infusional dose-adjusted etoposide, doxorubicin and cyclophosphamide with vincristine, prednisone and rituximab (DA-EPOCH-R) and filgrastim in untreated MGZL. We analyzed biomarkers of outcome and compared their clinical and biological characteristics to PMBL. Twenty-four MGZL patients had a median (range) age of 33 (14-59) years and 46% had mediastinal masses ≥ 10 cm. At 59 months median follow-up, the event-free survival and overall survival were 62% and 74%, respectively. The serum absolute lymphocyte count, the presence of tumor infiltrating dendritic cells, CD15 expression on the malignant cells and tumor morphology were biomarkers of outcome in MGZL. Compared with PMBL, MGZL patients were more likely to be male, express CD15, have lower expression of CD20 and to have a worse outcome. DA-EPOCH-R alone is effective in MGZL. The trial was registered at ClinicalTrials.Gov (NCT00001337).
- Quantification of target analytes in various biofluids using a postcolumn infused-internal standard method combined with matrix normalization factors in liquid chromatography-electrospray ionization mass spectrometry. [JOURNAL ARTICLE]
- J Chromatogr A 2014 Jun 30.
Liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) has become one of the most widely used methods in pharmaceutical laboratories. Although LC-ESI-MS provides high sensitivity and high specificity for quantifying target analytes in complicated biofluids, the associated severe matrix effects (MEs) generally result in large quantification errors. Here, we propose a novel strategy for correcting MEs in various biofluids using a postcolumn infused-internal standard (PCI-IS) method in combination with matrix normalization factors (MNFs). We used the MNFs to normalize the encountered MEs in various biofluids to the MEs encountered in standard solutions. The use of a postcolumn infused-internal standard also corrects the MEs for individual samples. When using the PCI-IS method in combination with MNFs, the calibration curve generated from standard solutions can be applied to quantify the target analytes in various biofluids. We applied this new approach to quantify etoposide and etoposide catechol in plasma and CSF. The accuracy of the test results showed that over 93% of the data have quantification errors less than 20% and that 99% of the data have quantification errors less than 30%. The successful application of this method to evaluate real clinical samples revealed that our proposed MNFs in combination with the PCI-IS method largely simplifies the entire method development and validation processes, saves a great deal of time and cost without sacrificing quantification accuracy, and provides a simple means of quantifying target analytes in various biofluids. This method will be particularly useful in fields in which the same target analytes need to be quantified in various types of matrices, including bioanalysis, forensic toxicology, environmental studies, and food safety control.
- Recurrent posterior reversible encephalopathy syndrome after chemotherapy in hematologic malignancy-posterior reversible encephalopathy syndrome can strike twice!!! [Journal Article]
- J Cancer Res Ther 2014 Apr-Jun; 10(2):393-6.
Posterior reversible encephalopathy syndrome (PRES) is a neuro-radiological syndrome characterized by seizures, altered level of consciousness, visual disturbance, and hyperintense lesions on magnetic resonance imaging most commonly in the posterior regions. PRES is typically associated with a number of complex clinical conditions including: Preeclampsia/eclampsia, allogeneic bone marrow transplantation, solid organ transplantation, autoimmune diseases, and high-dose anti-neoplastic therapy. We herein describe a case of recurrent PRES in a 29-year-old lady of refractory anaplastic large-cell lymphoma who was on second-line chemotherapy with Ifosfamide-Carboplatin-etoposide regimen. We have also tried to illustrate the pathogenesis, radiological features, and management of PRES. Although reversible in most cases, PRES may be recurrent even in chemotherapy - induced cases and result in fatal outcomes despite appropriate intervention. This is the first - reported case of recurrent PRES with such a fatal outcome, as a complication of anti-neoplastic systemic therapy.
- "On water" expedient synthesis of 3-indolyl-3-hydroxy oxindole derivatives and their anticancer activity in vitro. [JOURNAL ARTICLE]
- Eur J Med Chem 2014 Jul 7.:155-159.
A series of 3-indolyl-3-hydroxy oxindole derivatives (n = 41) were synthesized by the green aminocatalytic method with excellent yields under mild reaction conditions. All the newly synthesized derivatives were subjected to evaluate their cytotoxic properties against different human cancer cell lines. Results indicated that about 73% of the derivatives exhibited significant anti-proliferative activities against leukemia (U937, THP-1), lung (A549) and breast cancer (MCF7) cell lines. Among them a few of the derivatives exhibited the most potent and effective cytotoxic activities on U937 (34, 36, 38 and 41) and MCF7 (12, 35, 40 and 41) cell lines, and their anti-proliferation activities are better than the positive control, Etoposide.
- Primary choriocarcinoma of the posterior mediastinum in a male: A case report and review of the literature. [JOURNAL ARTICLE]
- Oncol Lett 2014 Aug; 8(2):739-741.
Primary choriocarcinoma of the posterior mediastinum is considered to be extremely rare, and the majority of these tumors occur in the gonads and uterus. The current study presents the case of a 40-year-old male who presented to the Department of Thoracic Surgery (Medical College of Yangzhou University, Yangzhou, China) with left chest pain for two months. Computed tomography of the chest showed a 4.9×5.2-cm mass in the posterior mediastinum and enlargement of the mediastinal lymph nodes. Resection of the tumor and upper lobe of the left lung was performed and the patient received combination chemotherapy with six courses of etoposide plus cisplatin. The patient recovered and was discharged. One year post surgery and chemotherapy, the patient was followed up and evidence of a recurrent tumor in the cerebrum was observed.
- Chk1 activity is required for BAK multimerization in association with PUMA during mitochondrial apoptosis. [JOURNAL ARTICLE]
- Cell Commun Signal 2014 Jul 10; 12(1):42.
BackgroundThe Bcl-2 protein BAK is a key player in mitochondrial apoptosis and responds to a myriad of different death signals. Activation of BAK is a multistep process that involves a number of conformational changes mediated by BH3-only proteins or p53 which leads to BAK multimerization and pore formation in the mitochondrial outer membrane. We previously reported that BAK activation is dependent upon dephosphorylation of both tyrosine and serine residues. Further, recent reports demonstrated that PP2A activity is required for BAK multimerization. Since Chk1, a checkpoint kinase involved in the activation of G2 checkpoint, is regulated by PP2A, we therefore hypothesized that Chk1 is involved in BAK multimerization during cell cycle arrest upon severe DNA damage.FindingsWe now show that treatment of HCT116-WT BAK cells with a Chk1 inhibitor impaired BAK dimerization and mutimerization when treated with the DNA damaging agents UV or etoposide. As a result there is a concomitant decrease of cytochrome c release from isolated mitochondria challenged with tBid protein and failure in the activation of caspase3. Interestingly, co-immunoprecipitation studies suggest that Chk1 is required for recruitment of BH3- only protein PUMA to BAK. We also showed that Chk1 is associated with BAK upon DNA damage.ConclusionThese findings novelly demonstrate the involvement of a checkpoint kinase Chk1 is required for BAK activation and underscores the importance of involvement of Chk1 in mitochondrial apoptosis upon severe DNA damage.