B-Acute lymphoblastic leukemia (B-ALL) represents a hematologic malignancy with poor clinical outcome and low survival rates in adult patients. Remission rates in Hispanic population are almost 30 % lower and ...
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τρίτη 5 Απριλίου 2016
High expression of ID family and IGJ genes signature as predictor of low induction treatment response and worst survival in adult Hispanic patients with B-acute lymphoblastic leukemia
Gastrointestinal perforation during neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in patients with esophageal cancer: a report of two cases
Abstract
Neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment for esophageal squamous cell carcinoma diagnosed as clinical stage II/III in Japan, and the indications for chemotherapy for esophageal cancer are increasing. Here, we report two patients who suffered from upper gastrointestinal perforation during NAC for esophageal cancer. NAC with cisplatin and 5-fluorouracil (CF regimen) was performed for both patients. Emergency operations were performed in all the patients prior to curative surgery for esophageal cancer. Endoscopic examination should be performed to confirm peptic ulcers or scars before NAC with CF regimen, and premedication with a proton pump inhibitor and the avoidance of steroid use are recommended for patients with a history of peptic ulcer to prevent perforation during NAC. Whether the occurrence of perforations during NAC is a risk factor for recurrence or a poor prognosis should be investigated in patients with esophageal cancer.
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Hematologic malignancies: newer strategies to counter the BCL-2 protein
Abstract
Introduction
BCL-2 is the founding member of the BCL-2 family of apoptosis regulatory proteins that either induce (pro-apoptotic) or inhibit (anti-apoptotic) apoptosis. The anti-apoptotic BCL-2 is classified as an oncogene, as damage to the BCL-2 gene has been shown to cause a number of cancers, including lymphoma. Ongoing research has demonstrated that disruption of BCL-2 leads to cell death. BCL-2 is also known to be involved in the development of resistance to chemotherapeutic agents, further underscoring the importance of targeting the BCL-2 gene in cancer therapeutics. Thus, numerous approaches have been developed to block or modulate the production of BCL-2 at the RNA level using antisense oligonucleotides or at the protein level with BCL-2 inhibitors, such as the novel ABT737.
Methods
In this article, we briefly review previous strategies to target the BCL-2 gene and focus on a new approach to silence DNA, DNA interference (DNAi).
Results and conclusion
DNA interference is aimed at blocking BCL-2 gene transcription. Evaluations of this technology in preclinical and early clinical studies are very encouraging and strongly support further development of DNAi as cancer therapeutics. A pilot phase II clinical trial in patients with relapsed or refractory non-Hodgkin lymphoma, PNT2258 demonstrated clinical benefit in 11 of 13 patients with notable responses in diffuse large B cell lymphoma and follicular lymphoma. By targeting the DNA directly, the DNAi technology promises to be more effective compared with other gene-interference strategies that target the RNA or protein but leaves the dysregulated DNA functional.
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Evidence for embryonic stem-like signature and epithelial-mesenchymal transition features in the spheroid cells derived from lung adenocarcinoma
Abstract
Identification of the cellular and molecular aspects of lung cancer stem cells (LCSCs) that are suggested to be the main culprit of tumor initiation, maintenance, drug resistance, and relapse is a prerequisite for targeted therapy of lung cancer. In the current study, LCSCs subpopulation of A549 cells was enriched, and after characterization of the spheroid cells, complementary DNA (cDNA) microarray analysis was applied to identify differentially expressed genes (DEGs) between the spheroid and parental cells. Microarray results were validated using quantitative real-time reverse transcription-PCR (qRT-PCR), flow cytometry, and western blotting. Our results showed that spheroid cells had higher clonogenic potential, up-regulation of stemness gene Sox2, loss of CD44 expression, and gain of CD24 expression compared to parental cells. Among a total of 160 genes that were differentially expressed between the spheroid cells and the parental cells, 104 genes were up-regulated and 56 genes were down-regulated. Analysis of cDNA microarray revealed an embryonic stem cell-like signature and over-expression of epithelial-mesenchymal transition (EMT)-associated genes in the spheroid cells. cDNA microarray results were validated at the gene expression level using qRT-PCR, and further validation was performed at the protein level by flow cytometry and western blotting. The embryonic stem cell-like signature in the spheroid cells supports two important notions: maintenance of CSCs phenotype by dedifferentiating mechanisms activated through oncogenic pathways and the origination of CSCs from embryonic stem cells (ESCs). PI3/AKT3, as the most common up-regulated pathway, and other pathways related to aggressive tumor behavior and EMT process can confer to the spheroid cells' high potential for metastasis and distant seeding.
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Impact of X-linked inhibitor of apoptosis protein on survival of nasopharyngeal carcinoma patients following radiotherapy
Abstract
This study aims to investigate CNE1 and CNE2 cell proliferation and apoptosis of nasopharyngeal cancer (NPC) and X-linked inhibitor of apoptosis protein (XIAP) expression in NPC patients after radiotherapy. Quantitative real-time quantitative polymerase chain reaction (qRT-PCR) and Western Blot detected XIAP and XIAP-associated factor1 (XAF1) messenger RNA (mRNA) and protein expression of CNE1 and CNE2 in NPC cells irradiated by γ-ray; MTT and flow cytometry assays detected CNE2 cells proliferation and apoptotic rate, respectively. With a retrospective analysis of 109 NPC patients in Xinxiang Central Hospital, immunohistochemistry (IHC) method detected XIAP expression, followed by a 5-year clinical analysis of the prognosis relevance after radiotherapy. In vitro, the inhibition and apoptotic rates of cells increased with the growth of radiation dose. qRT-PCR and Western blot detection declared that XIAP mRNA and protein expression increased, whereas XAF1 mRNA and protein expression decreased with the growth of radiation dose and exposure time. And XIAP mRNA and protein expression were negatively correlated with proliferation and apoptotic rates of the cells. In vivo, positive XIAP expression rate was negatively correlated with pathological tumor-node-metastasis (p-TNM) staging and tumor differentiation. Further, high XIAP expression, high p-TNM staging, and lower degree of differentiation were significantly correlated with the decrease of NPC patients' survival rate. Additionally, XIAP expression, p-TNM staging, and degrees of differentiation were independent risk factors for the survival of the NPC patients after radiotherapy. Increased XIAP expression and decreased XAF1 expression may be one reason for the apoptosis delays of CNE1 and CNE2 cells after irradiation, and the XIAP expression or the p-TNM staging and degree of differentiation are independent risk factors for NPC patients' survival after radiotherapy, providing a molecular rationale for radiotherapy and prognosis of NPC.
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Inhibition of protein methylesterase 1 decreased cancerous phenotypes in endometrial adenocarcinoma cell lines and xenograft tumor models
Abstract
Protein methylesterase 1 (PME-1) promotes cancerous phenotypes through the demethylation and inactivation of protein phosphatase 2A. We previously demonstrated that PME-1 overexpression promotes Akt, ERK, and may promote Wnt signaling and increases tumor burden in a xenograft model of endometrial cancer. Here, we show that covalent PME-1 inhibitors decrease cell proliferation and invasive growth in vitro but have no effect in vivo at the concentrations tested; however, depletion of PME-1 with shRNA in an endometrial cancer xenograft model significantly reduced tumor growth. Thus, discovery of more potent PME-1 inhibitors may be beneficial for the treatment of endometrial cancer.
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High miR-96 levels in colorectal adenocarcinoma predict poor prognosis, particularly in patients without distant metastasis at the time of initial diagnosis
Abstract
MicroRNA-96 (miR-96) is an oncomiR that facilitates the development of malignant tumors by promoting growth, proliferation, and survival of cancer cells. Previous studies using high-throughput techniques have shown that miR-96 is upregulated in colorectal cancer compared to adjacent normal colorectal tissue. The aim of this study was the investigation of the potential clinical value of miR-96 as a molecular prognostic biomarker in colorectal adenocarcinoma. For this purpose, total RNA was extracted from 108 primary colorectal adenocarcinoma samples and 54 paired non-cancerous colorectal tissue specimens. After polyadenylation and reverse transcription, miR-96 molecules were determined using an in-house developed real-time quantitative PCR based on SYBR Green chemistry. Calculations were carried out with the comparative CT method, using SNORD48 as endogenous reference gene. Finally, extensive biostatistical analysis was performed and showed that miR-96 is significantly upregulated in colorectal adenocarcinoma specimens compared to their non-cancerous counterparts (p < 0.001) as well as in tumors having invaded regional lymph nodes (p = 0.009) and those of advanced TNM stage (p = 0.008). miR-96 expression is an unfavorable prognostic marker in colorectal adenocarcinoma, predicting poor disease-free and overall survival (p = 0.041 and 0.028, respectively), independently of classical clinicopathological parameters. Most importantly, miR-96 expression stratifies patients without distant metastasis (M0) at the time of diagnosis into two groups with substantially different prognosis (p = 0.040). In conclusion, high tissue levels of miR-96 are associated with advanced stages of colorectal adenocarcinoma and predict an increased risk for disease recurrence and poor overall survival, especially in patients without distant metastasis at the time of diagnosis.
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Distinctive impact of pre-existing interstitial lung disease on the risk of chemotherapy-related lung injury in patients with lung cancer
Abstract
Purpose
Pre-existing interstitial lung disease (pre-ILD) increases the risk of chemotherapy-related lung injury (CRLI). However, whether the risk varies by type of anti-cancer cytotoxic agent in patients with pre-ILD is unknown. In this study, we hypothesized that S-1, an oral fluoropyrimidine agent, is associated with a smaller CRLI risk than docetaxel (DTX) and investigated these agents together with radiological evaluations of pre-ILD via pre-treatment chest computed tomography (CT).
Methods
After reviewing 234 and 352 patients who underwent evaluable chest CT within 6 months prior to the administration of S-1 or DTX, respectively, from January 2006 to October 2014, 60 and 89, respectively, of these patients with pre-ILD were retrospectively analysed.
Results
In total, 2 persons administered S-1 (3 %) and 16 treated with DTX (18 %) developed CRLI (p = 0.007) after the initial treatment (mean, 61 days), of whom 1 and 7, respectively, died because of respiratory failure. Pre-treatment CT revealed that 9 S-1-treated patients (16 %) and 15 DTX-treated patients (17 %) had pre-ILD occupying more than 25 % of the lung field. Multivariate analysis demonstrated that DTX administration increased the risk of CRLI by 6.47-fold versus S-1 therapy (p = 0.016). Of note, the area occupied by pre-ILD was also associated with the risk of CRLI (<25 %; odds ratio 0.309, p = 0.045).
Conclusions
Our results indicated that S-1 is associated with a smaller risk of CRLI than DTX. The area occupied by pre-ILD should also be noted when administrating anti-cancer agents.
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Analysis of a single-codon E746 deletion in exon 19 of the epidermal growth factor receptor
Abstract
Purpose
Epidermal growth factor receptor (EGFR) gene mutations are the most established genomic biomarkers for the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). The most frequent deletion in exon 19 is delE746_750, followed by del747_753insS and del747_750insP. Since investigations of delE746 have not been reported previously, it is unclear if delE746 conveys sensitivity to TKI effect of TKI on EGFR delE746. The objective was to characterize delE746 of the EGFR gene and to explore the effects of TKIs on the delE746.
Methods
We assessed the ability of gefitinib to inhibit phosphorylation of clonal L929 cell lines expressing EGFR with delE746. 3-D structures of the EGFR proteins were also used to investigate the interaction with gefitinib.
Results
The delE746 mutant EGFR-expressing cells exhibited gefitinib-sensitive autophosphorylation, which altered the structure of the EGFR and increased the instances of docking during docking simulations of gefitinib with the EGFR-TK. This mutant revealed that it exhibited molecular conformation alterations, and more frequent binding with gefitinib compared to wild-type EGFR. We administered EGFR-TKI, gefitinib to a Japanese woman with lung cancer that contained delE746. The patient achieved partial response after a 5 month of treatment with gefitinib.
Conclusion
Our study revealed biological, structural, and probably clinical features of the delE746 form of EGFR.
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Trends in incidence, survival and mortality of childhood and adolescent cancer in Austria, 1994–2011
Publication date: June 2016
Source:Cancer Epidemiology, Volume 42
Author(s): Henrike E. Karim-Kos, Monika Hackl, Georg Mann, Christian Urban, Adelheid Woehrer, Irene Slavc, Ruth Ladenstein
BackgroundThis is the first study on trends in cancer incidence, survival and mortality for children and adolescents in Austria. The aim was to assess to what extent progress against childhood and adolescent cancer has been made in Austria since the 1990s and to complement the childhood and adolescent cancer trends for Central Europe.MethodsAll malignant neoplasms and non-malignant tumours of the Central Nervous System (CNS) in patients aged less than 20 years and diagnosed between 1994 and 2011 (N=5425) were derived from the Austrian National Cancer Registry (ANCR). Incidence and mortality trends were evaluated by the average annual percentage change (AAPC). Observed survival rates were calculated based on follow-up until December 31st 2013.ResultsChildhood cancer remained stable with 182 cases per million in 2011, but rose among girls by 1.4% (95% CI: .1, 3.6) annually due to an increase of non-malignant CNS tumours and Non-Hodgkin lymphoma. Adolescent cancer rose by 1.5% (95% CI: .4, 2.6) annually, from 182 cases per million in 1994–269 in 2011, especially leukaemia, CNS tumours (including non-malignant types) and epithelial tumours. Five-year survival improved by 5–7% reaching 86% for both groups (p<.05). Mortality declined by −2.4% (95% CI: −3.7, −1.2) and −2.0% (95% CI: −4.6, .5), respectively, especially for childhood leukaemia.ConclusionProgress is demonstrated by improved survival and declined mortality most likely related to improved diagnostic techniques, more effective therapeutic regimes, supportive care and a central advisory function of experts in the Austrian paediatric oncology.
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Impact of β-glucan on the Fecal Water Genotoxicity of Polypectomized Patients.
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Impact of β-glucan on the Fecal Water Genotoxicity of Polypectomized Patients.
Nutr Cancer. 2016 Apr 4;:1-8
Authors: Turunen KT, Pletsa V, Georgiadis P, Triantafillidis JK, Karamanolis D, Kyriacou A
Abstract
The aim of the study was to determine the effect of β-glucan on the cytotoxicity and genotoxicity of polypectomized patient's fecal water (FW). Polypectomized volunteers (n = 69) were randomly assigned to consume bread with or without β-glucan, for 3 months. FW was collected at the beginning (t = 0), the 30th and 90th day and 2 wk after the intervention. Cytotoxicity and genotoxicity were estimated on Caco-2 cells, using trypan blue exclusion test and comet assay, respectively. Gastrointestinal symptoms were recorded and subjects kept a 3-day food diary at baseline and after completion. Trypan blue exclusion test revealed cell survival of approximately 87% after incubation with FW. The FW samples showed 49% genotoxicity at the baseline. Genotoxicity in the intervention group decreased during the trial reaching statistical significance on the 90th day compared to control. An increase was noticed 2 wk after the trial, but it still remained significantly lower compared to control. Group-specific analysis for β-glucan also revealed significant decrease in the genotoxicity on the 90th day compared to baseline. β-glucan ingestion in polypectomized patients significantly decreased the genotoxicity of their FW. Our findings suggest that β-glucan consumption could possibly provide protection against colon cancer development.
PMID: 27043932 [PubMed - as supplied by publisher]
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Dietary Fatty Acids from Leaves of Clerodendrum Volubile Induce Cell Cycle Arrest, Downregulate Matrix Metalloproteinase-9 Expression, and Modulate Redox Status in Human Breast Cancer.
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Dietary Fatty Acids from Leaves of Clerodendrum Volubile Induce Cell Cycle Arrest, Downregulate Matrix Metalloproteinase-9 Expression, and Modulate Redox Status in Human Breast Cancer.
Nutr Cancer. 2016 Apr 4;:1-12
Authors: Erukainure OL, Zaruwa MZ, Choudhary MI, Naqvi SA, Ashraf N, Hafizur RM, Muhammad A, Ebuehi OA, Elemo GN
Abstract
The antiproliferative effect of the fatty acid components of Clerodendrum volubile leaves as well as its antioxidant effect on MCF-7 and MDA-MB-231 human breast cancer cell lines were investigated. Fatty acids extracted from C. volubile leaf oil were subjected to gas chromatography mass spectrometry (GCMS) analysis. The cells were cultured and treated with the fatty acids for 48 h, after which the antiproliferation effect was ascertained via MTT assay and cell viability analysis using BD fluorescence activated cells sorting (FACS) Calibur. Cell cycle was analyzed by flow cytometry on FACS Calibur. Western blotting was used in determining expression of proteins in the cell lines. The treated cell lines were assessed for reduced glutathione level, catalase, superoxide dismutase, and lipid peroxidation. The fatty acids significantly inhibited cell proliferation, arrested G0/G1 phase, downregulated the expression of MMP-9, and attenuated oxidative stress in of MCF-7 cell lines but had little or no effect on MDA-MB-231 cell lines. These results indicate the therapeutic potential of the fatty acids components of the leaves of C. volubile on human breast cancer, which may be explored further in drug development.
PMID: 27043182 [PubMed - as supplied by publisher]
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Glycone-rich Soy Isoflavone Extracts Promote Estrogen Receptor Positive Breast Cancer Cell Growth.
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Glycone-rich Soy Isoflavone Extracts Promote Estrogen Receptor Positive Breast Cancer Cell Growth.
Nutr Cancer. 2016 Apr 4;:1-12
Authors: Johnson KA, Vemuri S, Alsahafi S, Castillo R, Cheriyath V
Abstract
Due to the association of hormone replacement therapy (HRT) with breast cancer risk, estrogenically active soy isoflavones are considered as an HRT alternative to alleviate menopausal symptoms. However, several recent reports challenged the health benefits of soy isoflavones and associated them with breast cancer promotion. While glyconic isoflavones are the major constituents of soybean seeds, due to their low cell permeability, they are considered to be biologically inactive. The glyconic isoflavones may exert their effects on membrane-bound estrogen receptors or could be converted to aglycones by extracellular β-glucosidases. Therefore, we hypothesized that despite their low cell permeability, soybean cultivars with high glyconic isoflavones may promote breast cancer cell growth. To test this, composition and estrogenic activity of isoflavones from 54 commercial soybean cultivars were determined. Soybean seeds produced in identical climate and growth conditions were used to minimize the effects of extraneous factors on isoflavone profile and concentrations. The glyconic daidzin concentration negatively correlated with genistin and with other aglycones. Relative to control, isoflavone extracts from 51 cultivars were estrogenic and promoted the growth of estrogen receptor positive (ER+) breast cancer cell line MCF-7 from 1.14 to 4.59 folds and other three cultivars slightly reduced the growth. Among these, extracts from three cultivars were highly estrogenic and promoted MCF-7 cell growth by 2.59-4.64 folds (P<0.005). Among six isoflavones, daidzin was positively associated with MCF-7 cell growth (P<0.005, r = 0.13966), whereas the negative correlation between genistin and MCF-7 cell growth was nearly significant (P≤0.0562, r = -0.026141). Furthermore, in drug interaction studies daidzin-rich isoflavone extracts antagonized tamoxifen, an ER inhibitor. Taken together, our results suggest that the glyconic daidzin-rich soy isoflavone extracts may exert estrogenic effects and promote ER+ breast cancer growth.
PMID: 27043076 [PubMed - as supplied by publisher]
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Simvastatin Reduces Cancerogenic Potential of Renal Cancer Cells via Geranylgeranyl Pyrophosphate and Mevalonate Pathway.
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Simvastatin Reduces Cancerogenic Potential of Renal Cancer Cells via Geranylgeranyl Pyrophosphate and Mevalonate Pathway.
Nutr Cancer. 2016 Apr 4;:1-8
Authors: Woschek M, Kneip N, Jurida K, Marzi I, Relja B
Abstract
Simvastatin is a cholesterol-lowering drug, inhibiting 3-hydroxy-3-methylglutaryl-coenzyme CoA (HMG-CoA) reductase. Previous studies have indicated the anticancerous effects of simvastatin. Here, we evaluated the anticancerous potential of simvastatin in renal cell carcinoma (RCC) cell lines. RCC occurs with an incidence of 2-3% of all cancer entities with high chemoresistance rate. Therefore, the understanding of underlying mechanisms for RCC activity and the development of alternative therapies are essential. Human RCC cell lines Caki-1 and KTC-26 were treated with simvastatin (16 or 33 µM) for 48 or 72 h. The effects of the downstream substrates mevalonate (MA), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) were evaluated using add-back experiments. Cell growth was assessed using MTT assay. Apoptosis and cell cycle were analyzed by flow cytometry. Apoptosis-involved proteins were evaluated by Western blot. Simvastatin caused dose- and time-dependent inhibition of RCC cell growth by cell cycle arrest and apoptosis induction. Substitution of MA or GGPP abolished these effects to a large extent. These findings suggest that the antiproliferative effects of simvastatin are not only mediated through cholesterol deprivation but also by prenylation-associated mechanisms, thereby providing new insights into tumor-suppressive ability of simvastatin and into novel additive treatment options in the management of RCC.
PMID: 27042994 [PubMed - as supplied by publisher]
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Young Barley Indicates Antitumor Effects in Experimental Breast Cancer In Vivo and In Vitro.
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Young Barley Indicates Antitumor Effects in Experimental Breast Cancer In Vivo and In Vitro.
Nutr Cancer. 2016 Apr 4;:1-11
Authors: Kubatka P, Kello M, Kajo K, Kruzliak P, Výbohová D, Šmejkal K, Maršík P, Zulli A, Gönciová G, Mojžiš J, Kapinová A, Murin R, Péč M, Adamkov M, Przygodzki RM
Abstract
The effect of dietary administered young barley containing a mixture of phytochemicals to female rats for the prevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis was evaluated. After carcinogen administration (14 wk), mammary tumors were removed and prepared for histopathological and immunohistochemical analysis. Moreover, in vitro evaluation of possible mechanisms in MCF-7 breast cancer cell line was performed. Barley (0.3%) demonstrated mild antitumor effect in mammary carcinogenesis, yet 3% barley did not further improve this effect. Immunohistochemical analysis of rat tumor cells in treated groups showed significant increase in caspase-3 expression and significant reduction in Ki67 expression. In addition, 3% barley significantly decreased dityrosine levels versus control. Barley in higher dose significantly decreased serum low-density lipoprotein-cholesterol in rats. In vitro studies showed that barley significantly decreased survival of MCF-7 cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and significantly decreased 5-bromo-20-deoxyuridine incorporation versus control. Barley prevented cell cycle progression and extended incubation with barley showed significant increase in the percentage of annexin V/propidium iodide-positive MCF-7 cells. Our results propose an antitumor effect for the mixture of phytochemicals present in young barley in a breast cancer model.
PMID: 27042893 [PubMed - as supplied by publisher]
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Stage-specific Dietary Factors Associated with the Correa Multistep and Multifactorial Process of Human Gastric Carcinogenesis.
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Stage-specific Dietary Factors Associated with the Correa Multistep and Multifactorial Process of Human Gastric Carcinogenesis.
Nutr Cancer. 2016 Apr 4;:1-13
Authors: Hsiung HY, Fann JC, Yen AM, Chen SL, Chiu SY, Ku TH, Liu TY, Chen HH, Lin MW
Abstract
We assessed how individual dietary intakes act at different points in the chain of sequential stage of the Correa model in an area of Taiwan with high incidence of gastric cancer (GC). Using data on 2,201 participants in a two-stage screening for gastric neoplasia with pepsinogen test, we identified 154 superficial gastritis (SG), 32 atrophic gastritis (AG), 117 intestinal metaplasia (IM), and 22 GC. Effects of individual item-based and construct-based dietary variables aggregated by factor analysis on each stage of gastric neoplasm were assessed. Based on 1,211 subjects with complete information on serological test and dietary questionnaire, SG was associated with positive quartile trend for the intake of meat (trend test P = 0.0014) and the intake of fruits and leafy vegetables (trend test P = 0.0177), but with the negative trend for the intake of shrimp sauce (trend test P = 0.039). A significant positive association was noted between milk and AG (trend test P = 0.014) and IM (P = 0.0087). A positive association between seafood and IM was noted (P = 0.011). Frequent leafy vegetable intake based on individual item was inversely associated with GC (P = 0.0084), whereas frequent intake of meat showed a high positive association (P<0.001). Stage-specific dietary factors underpinning the Correa model were identified.
PMID: 27042805 [PubMed - as supplied by publisher]
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Grifola frondosa Glycoprotein GFG-3a Arrests S phase, Alters Proteome, and Induces Apoptosis in Human Gastric Cancer Cells.
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Grifola frondosa Glycoprotein GFG-3a Arrests S phase, Alters Proteome, and Induces Apoptosis in Human Gastric Cancer Cells.
Nutr Cancer. 2016 Feb-Mar;68(2):267-79
Authors: Cui F, Zan X, Li Y, Sun W, Yang Y, Ping L
Abstract
GFG-3a is a novel glycoprotein previously purified from the fermented mycelia of Grifola frondosa with novel sugar compositions and protein sequencing. The present study aims to investigate its effects on the cell cycle, differential proteins expression, and apoptosis of human gastric cancer SGC-7901 cells. Our findings revealed that GFG-3a induced the cell apoptosis and arrested cell cycle at S phase. GFG-3a treatment resulted in the differential expression of 21 proteins in SGC-7901 cells by upregulating 10 proteins including RBBP4 associated with cell cycle arrest and downregulating 11 proteins including RUVBL1, NPM, HSP90AB1, and GRP78 involved in apoptosis and stress response. qRT-PCR and Western blot analysis also suggested that GFG-3a could increase the expressions of Caspase-8/-3, p53, Bax, and Bad while decrease the expressions of Bcl2, Bcl-xl, PI3K, and Akt1. These results indicated that the stress response, p53-dependent mitochondrial-mediated, Caspase-8/-3-dependent, and PI3k/Akt pathways were involved in the GFG-3a-induced apoptosis process in SGC-7901 cells. These findings might provide a basis to prevent or treat human gastric cancer with GFG-3a and understand the tumor-inhibitory molecular mechanisms of mushroom glycoproteins.
PMID: 27040446 [PubMed - in process]
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["SOS SEIN 84" accelerated breast disease management: Patients satisfaction survey].
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["SOS SEIN 84" accelerated breast disease management: Patients satisfaction survey].
Bull Cancer. 2016 Mar 31;
Authors: Arnaud A, Dumuids M, Mège A, de Rauglaudre G, Regis Arnaud A, Martin N, Dupuy Meurat F, Dolle S, Gallon E, Serin D
Abstract
In case of a new breast symptom or an abnormal result of breast imaging, some women have a problem finding a quick answer to allay their anxiety. The Institut Sainte-Catherine in Avignon has set up a new form of accelerated disease management through the opening of a new dedicated consultation called SOS SEIN 84. We present the result of a prospective quality study of our first new patients.
PMID: 27040268 [PubMed - as supplied by publisher]
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AZD9291 overcomes T790 M-mediated resistance through degradation of EGFR L858R/T790M in non-small cell lung cancer cells
Summary
The discovery of activating mutations of epidermal growth factor receptor (EGFR) has resulted in the development of more effective treatments for non-small cell lung cancer (NSCLC). Although first-generation EGFR tyrosine kinase inhibitors (EGFR TKIs) provide significant clinical benefit, acquired resistance often occurs, most commonly (>50 %) via a T790 M resistance mutation. Although AZD9291 is selective for both T790 M and activating EGFR mutations over wild-type EGFR, it is highly active when T790 M is present, especially EGFRL858R/T790M, and modestly active when T790 M is absent. The aim of this study was to elucidate the underlying mechanism of the high sensitivity of NSCLC cells harboring EGFRL858R/T790M to AZD9291. In H1975 cells harboring EGFRL858R/T790M, AZD9291 potently inhibited cellular growth and EGFR signaling pathways together with depletion of mutant EGFR protein. AZD9291-induced depletion of EGFRL858R/T790M protein was abrogated through inhibition of the proteasome with MG132. However, AZD9291 had no effect on protein levels of EGFRWT and EGFRL858R. In addition, AZD9291 induced apoptosis and caused expression changes in cell cycle-related genes. Moreover, oral administration of AZD9291 as a single agent induced tumor regression in vivo in a H1975 tumor xenograft model and reduced EGFRL858R/T790M protein levels in xenograft tumors. Taken together, our results provide a potential mechanism for the sensitivity of EGFRL858R/T790M cells to AZD9291 and suggest that AZD9291 may be effective in cases of T790 M-positive EGFR resistance.
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Mechanisms and Therapeutic Targets of microRNA-associated Chemoresistance in Epithelial Ovarian Cancer.
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Mechanisms and Therapeutic Targets of microRNA-associated Chemoresistance in Epithelial Ovarian Cancer.
Curr Cancer Drug Targets. 2016 Apr 4;
Authors: Zhang L, Nadeem L, Connor K, Xu G
Abstract
Epithelial ovarian cancer (EOC) is the most lethal disease among gynecologic malignancies. Despite increasing knowledge of ovarian cancer biology and advances in treatment efficacy, the survival rate of patients with EOC has not improved over the past two decades. Patients with an advanced disease often relapse due to the development of chemoresistance. Recent in vivo and in vitro studies have shown insight into the mechanisms of such drug resistance, including a potential role for microRNAs (miRNA, miR) in the process of chemoresistance. In this review, we provide an overview of current therapeutic targets of miRNA-associated chemoresistance in EOC and discuss potentially therapeutic values and molecular mechanisms by which miRNAs influence the development and reversal of chemoresistance.
PMID: 27040353 [PubMed - as supplied by publisher]
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CD34 expression modulates tube-forming capacity and barrier properties of peripheral blood-derived endothelial colony-forming cells (ECFCs)
Abstract
Endothelial colony-forming cells (ECFC) are grown from circulating CD34+ progenitors present in adult peripheral blood, but during in vitro expansion part of the cells lose CD34. To evaluate whether the regulation of CD34 characterizes the angiogenic phenotypical features of PB-ECFCs, we investigated the properties of CD34+ and CD34− ECFCs with respect to their ability to form capillary-like tubes in 3D fibrin matrices, tip-cell gene expression, and barrier integrity. Selection of CD34+ and CD34− ECFCs from subcultured ECFCs was accomplished by magnetic sorting (FACS: CD34+: 95 % pos; CD34−: 99 % neg). Both fractions proliferated at same rate, while CD34+ ECFCs exhibited higher tube-forming capacity and tip-cell gene expression than CD34− cells. However, during cell culture CD34− cells re-expressed CD34. Cell-seeding density, cell–cell contact formation, and serum supplements modulated CD34 expression. CD34 expression in ECFCs was strongly suppressed by newborn calf serum. Stimulation with FGF-2, VEGF, or HGF prepared in medium supplemented with 3 % albumin did not change CD34 mRNA or surface expression. Silencing of CD34 with siRNA resulted in strengthening of cell–cell contacts and increased barrier function of ECFC monolayers as measured by ECIS. Furthermore, CD34 siRNA reduced tube formation by ECFC, but did not affect tip-cell gene expression. These findings demonstrate that CD34+ and CD34− cells are different phenotypes of similar cells and that CD34 (1) can be regulated in ECFC; (2) is positively involved in capillary-like sprout formation; (3) is associated but not causally related to tip-cell gene expression; and (4) can affect endothelial barrier function.
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Genital invasion or perigenital spread may pose a risk of marginal misses for Intensity Modulated Radiotherapy (IMRT) in anal cancer
Abstract
Background
While intensity modulated radiotherapy (IMRT) in anal cancer is feasible and improves high-dose conformality, the current RTOG/AGITG contouring atlas and planning guidelines lack specific instructions on how to proceed with external genitalia. Meanwhile, the RTOG-Protocol 0529 explicitly recommends genital sparing on the basis of specific genital dose constraints. Recent pattern-of-relapse studies based on conventional techniques suggest that marginal miss might be a potential consequence of genital sparing. Our goal is to outline the potential scope and increase the awareness for this clinical issue.
Methods
We present and discuss four patients with perigenital spread in anal cancer in both early and advanced stages (three at time of first diagnosis and one in form of relapse). Genital/perigenital spread was observed once as direct genital infiltration and thrice in form of perigenital lymphatic spread.
Results
We review the available data regarding the potential consequences of genital sparing in anal cancer. Pattern-of-relapse studies in anal cancer after conventional radiotherapy and the current use of IMRT in anal cancer are equivocal but suggest that genital sparing may occasionally result in marginal miss. An obvious hypothesis suggested by our report is that perigenital lymphovascular invasion might be associated with manifest inguinal N+ disease.
Conclusions
Local failure has low salvage rates in recent anal cancer treatment series. Perigenital spread may pose a risk of marginal misses in IMRT in anal cancer. To prevent marginal misses, meticulous pattern-of-relapse analyses of controlled IMRT-series are warranted. Until their publication, genital sparing should be applied with caution, PET/CT should be used when possible and meeting genital dose constraints should not be prioritized over CTV coverage, especially (but not only) in stage T3/4 and N+ disease.
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Selumetinib for the treatment of metastatic uveal melanoma: past and future perspectives
Future Oncology Ahead of Print.
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MRI findings of post-traumatic subperiosteal hematoma of the iliac bone with resultant femoral nerve palsy in an adolescent boy
Abstract
Post-traumatic subperiosteal hematoma of the iliac bone may present insidiously without external evidence of bleeding or go undetected in the acute setting. In some cases, the patient may come to medical attention due to femoral nerve palsy rather than hip or groin pain. In this report, we describe a case of femoral nerve palsy caused by acute post-traumatic subperiosteal hematoma of the iliac bone using MRI to highlight the subperiosteal location. Anatomy of the femoral nerve is also discussed.
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CT-defined phenotype of pulmonary artery stenoses in Alagille syndrome
Abstract
Background
Alagille syndrome is a rare disorder commonly associated with pulmonary artery stenosis. Studies exist discussing the cardiovascular sequela but no consistent phenotype, or pattern of pulmonary artery stenosis, has been described.
Objective
The objective of this study was to characterize the distribution and severity of pulmonary artery stenosis in patients with Alagille syndrome based on computed tomography angiography.
Materials and methods
A retrospective chart review identified patients with Alagille syndrome who had undergone CT angiography. Pulmonary trunk (MPA), left main pulmonary artery (LPA) and right main pulmonary artery (RPA) diameters in Alagille patients were compared with those from matched control subjects. Stenoses at lobar and segmental pulmonary arteries were categorized as: Grade 1 (<33% stenosis), Grade 2 (33-66% stenosis) or Grade 3 (>66% stenosis). Involvement among the different lung regions was then compared.
Results
Fifteen patients ages 6 months to 17 years were identified; one had surgical augmentation of the central pulmonary arteries and was excluded from the central (main, right and left) pulmonary artery analysis. The proximal LPA and RPA, but not the MPA, were significantly smaller than those of the control subjects (P<0.01). The proximal LPA was significantly smaller than the proximal RPA (P<0.01) in the Alagille group (0.55 LPA:RPA ratio). Within the Alagille group, 75% of the lobar and segmental branches showed mild or no stenoses (Grade 1), 17% showed moderate stenosis (Grade 2) and 8% showed severe stenosis (Grade 3). While not statistically significant, the right lung demonstrated a greater percentage of Grades 2 and 3 stenoses (28%, right vs. 20% left, P=0.1). The right middle and lingula lobes of both lungs showed more Grade 2 and 3 stenoses (33% upper/middle vs. 18% lower, P<0.01).
Conclusion
We describe a common pattern pulmonary artery stenosis in Alagille patients consisting of severe proximal LPA stenosis, heavy involvement of the lobar and segmental branches (more often right than left), and a greater involvement of the upper lobes. Knowledge of this phenotypic pattern can help in the diagnosis of Alagille syndrome in patients presenting with pulmonary artery stenosis.
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Safety of gadobutrol in more than 1,000 pediatric patients: subanalysis of the GARDIAN study, a global multicenter prospective non-interventional study
Abstract
Background
Gadobutrol is a gadolinium-based contrast agent, uniquely formulated at 1.0 mmol/ml. Although there is extensive safety evidence on the use of gadobutrol in adults, few studies have addressed the safety and tolerability of gadobutrol in pediatric patients.
Objective
This subanalysis of data from the GARDIAN study evaluated the safety and use of gadobutrol in pediatric patients (age <18 years).
Materials and methods
The GARDIAN study was a large phase IV non-interventional prospective multicenter post-authorization safety study performed in Europe, Asia, North America and Africa. A total of 23,708 patients were included who were scheduled to undergo cranial or spinal MRI, liver or kidney MRI, or MR angiography with gadobutrol enhancement. The primary study endpoint was the overall incidence of adverse drug reactions (ADRs) and serious adverse events (SAEs) following gadobutrol administration.
Results
The GARDIAN study included 1,142 children (age <18 years) who received gadobutrol at a mean dose of 0.13 (range 0.04–0.50) mmol/kg body weight. Gadobutrol was well tolerated in these children, with low rates of ADRs (0.5%) and no SAEs, consistent with results in adults enrolled in the GARDIAN study. Rates of adverse events and ADRs were unrelated to pediatric age or gadobutrol weight-adjusted dose. There were no symptoms suggestive of nephrogenic systemic fibrosis. Investigators rated the contrast quality of gadobutrol-enhanced images as good or excellent in 97.8% of pediatric patients, similar to the main study population.
Conclusion
Gadobutrol is very well tolerated and provides excellent contrast quality at the recommended weight-adjusted dose in children (age <18 years), similar to the profile in adults.
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Imaging of primary pediatric lymphoma of bone
Abstract
Background
Primary pediatric bone lymphoma is a rare form of non-Hodgkin lymphoma. Unlike nodal forms of lymphoma, imaging abnormalities in lymphoma of bone do not resolve rapidly in conjunction with treatment and radiologic findings can remain abnormal for years, making it difficult to evaluate treatment response.
Objective
To evaluate the utility of imaging in assessment of patients with primary pediatric bone lymphoma.
Materials and methods
At our institution between 2004 and 2013, six cases of pathology-proven primary pediatric bone lymphoma were diagnosed. Retrospective chart review was performed to assess imaging utilization. Our data were qualitatively compared with existing literature to construct an algorithm for imaging patients with primary lymphoma of bone.
Results
Imaging evaluation of patients with primary pediatric bone lymphoma was highly variable at our institution. Conventional imaging was routinely used to evaluate response to treatment, despite lack of appreciable osseous change. Imaging in the absence of symptoms did not alter clinical management. Only positron emission tomography CT (PET/CT) proved capable of demonstrating imaging changes from the pretreatment to the post-treatment scans that were consistent with the clinical response to treatment.
Conclusion
Surveillance imaging is likely unnecessary in patients with a known diagnosis of pediatric lymphoma of bone. Pretreatment and post-treatment PET/CT is likely sufficient to assess response. There is little data to support the use of interim and surveillance PET/CT.
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Lesional perfusion abnormalities in Leigh disease demonstrated by arterial spin labeling correlate with disease activity
Abstract
Background
Leigh disease is a metabolic disorder of the mitochondrial respiratory chain culminating in symmetrical necrotizing lesions in the deep gray nuclei or brainstem. Apart from classic gliotic/necrotic lesions, small-vessel proliferation is also characteristic on histopathology. We have observed lesional hyperperfusion on arterial spin-labeling (ASL) sequence in children with Leigh disease.
Objective
In this cross-sectional analysis, we evaluated lesional ASL perfusion characteristics in children with Leigh syndrome.
Materials and methods
We searched the imaging database from an academic children's hospital for "arterial spin labeling, perfusion, necrosis, lactate, and Leigh" to build a cohort of children for retrospective analysis. We reviewed each child's medical record to confirm a diagnosis of Leigh disease, excluding exams with artifact, technical limitations, and without ASL images. We evaluated the degree and extent of cerebral blood flow and relationship to brain lesions. Images were compared to normal exams from an aged-matche cohort.
Results
The database search yielded 45 exams; 30 were excluded. We evaluated 15 exams from 8 children with Leigh disease and 15 age-matched normal exams. In general, Leigh brain perfusion ranged from hyperintense (n=10) to hypointense (n=5). Necrotic lesions appeared hypointense/hypoperfused. Active lesions with associated restricted diffusion demonstrated hyperperfusion. ASL perfusion patterns differed significantly from those on age-matched normal studies (P=<.0001). Disease activity positively correlated with cerebral deep gray nuclei hyperperfusion (P=0.0037) and lesion grade (P=0.0256).
Conclusion
Children with Leigh disease have abnormal perfusion of brain lesions. Hyperperfusion can be found in active brain lesions, possibly associated with small-vessel proliferation characteristic of the disease.
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Tiotropium Respimat ® Versus HandiHaler ® : Comparison of Bronchodilator Efficacy of Various Doses in Clinical Trials
Abstract
Introduction
The long-acting muscarinic antagonist tiotropium bromide is approved in many countries as maintenance therapy for chronic obstructive pulmonary disease (COPD). Tiotropium is available as a dry-powder formulation delivered via HandiHaler® (18 μg once daily) and is now also approved as an aqueous solution delivered via the Respimat® Soft Mist™ Inhaler (5 μg once daily, 2 puffs of 2.5 µg). Several studies have compared the efficacy of tiotropium HandiHaler (18 μg once daily) with different doses of Respimat. We aimed to compare available bronchodilator efficacy data of once-daily Respimat 1.25, 2.5, 5, 10, 20 µg, and HandiHaler 18 µg to investigate which dose of tiotropium delivered by Respimat is the closest match to tiotropium HandiHaler.
Methods
Evaluation of six clinical trials (duration from 3 weeks to 2–3 years) that included lung function measures (trough forced expiratory volume in 1 s and trough forced vital capacity) as key outcomes.
Results
In the six trials, bronchodilator efficacy of Respimat 5 μg and HandiHaler 18 μg was similar; however, reduced bronchodilator efficacy was observed with lower doses of Respimat (1.25 and 2.5 μg).
Conclusion
These findings support the use of the marketed once-daily dose of Respimat 5 μg for the maintenance treatment of patients with COPD.
Funding
Boehringer Ingelheim.
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FP/FORM Versus FP/SAL Within Clinical Practice: An Updated Budget Impact Analysis in Asthma
Abstract
Introduction
Pressurized metered-dose inhalers (pMDI) such as fluticasone propionate and salmeterol (FP/SAL) are commonly used for the treatment of asthma in the UK. Previously, a budget impact analysis demonstrated that use of FP and formoterol fumarate (FP/FORM) pMDI as an alternative to FP/SAL pMDI, would be a cost-saving option for the UK National Health Service (NHS). This budget impact analysis aimed to update the existing analysis with prescription volume data and real-world evidence since the introduction of FP/FORM to the UK market.
Methods
Patient Data (IMS Information Solutions UK Ltd) moving annual total (MAT) August 2015 were used to ascertain the number of units of pMDI prescribed. Annual costs to the NHS in terms of drug, administration, monitoring and adverse event costs, were used to estimate the potential budget impact for FP/FORM and FP/SAL. Costs were calculated for current prescription volumes (12% FP/FORM, 88% FP/SAL), and for different prescription volume scenarios (FP/FORM at 0%, 25%, 50% and 100%). Real-world evidence and budget impact at a clinical commissioning group (CCG) level were also considered.
Results
Total annual costs per person year were less with FP/FORM (£625) than with FP/SAL (£734). Annual costs to the NHS based on the current prescription volumes and clinical trial data were estimated at £210.0M, however, based on real-world evidence, costs were estimated at £179.8M. For all scenarios with increased FP/FORM prescription volumes, the annual total costs to the NHS decreased. This was reflected at a CCG level.
Conclusion
The use of FP/FORM as an alternative to FP/SAL can result in cost savings for the NHS when assessing drug, administration, monitoring and adverse events costs. The inclusion of data released since the launch of FP/FORM within the budget impact analysis demonstrates that the potential cost savings to the NHS that were previously published are being translated to clinical practice.
Funding
Mundipharma, UK.
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Laparoscopic Sleeve Gastrectomy Improves Excessive Daytime Sleepiness and Sleep Quality 6 Months Following Surgery: A Prospective Cohort Study
Abstract
Introduction
Obstructive sleep apnea (OSA) is one of the most important co-morbid conditions related with morbid obesity. Bariatric procedures are associated with significant improvement in OSA. The aim of the current study was to evaluate the effect of bariatric surgery on daytime sleepiness and quality of sleep in patients that had undergone laparoscopic sleeve gastrectomy.
Methods
Fifty-nine patients were prospectively enrolled in the study. Pre-operative and post-operative (6 months) demographics, medical history, weight, and height of the patients were recorded, and patients were asked to complete Pittsburg Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) questionnaires. OSA screenings were performed using the STOP-Bang questionnaire.
Results
The mean age of the patients was 37.1 ± 1.2 years and 76% were female. Pre-operative and post-operative median (range) BMIs were 47 kg/m2 (39–67 kg/m2) and 35 kg/m2 (25–44 kg/m2), respectively (P < 0.001). The mean ± standard deviation excess weight loss was 51.6 ± 13.2%. In univariate analysis, total PSQI, STOP-Bang, and ESS scores were found to significantly improve 6 months after surgery (all P < 0.001). Multivariate mixed-model analysis showed a high correlation between the decrease in BMI and all key predictors. Mixed-model analysis revealed that every 1 kg/m2 decrease in BMI was associated with a 0.32, 0.13, and 0.26 improvements in PSQI, STOP-Bang, and ESS scores, respectively (all P < 0.001).
Conclusion
Laparoscopic sleeve gastrectomy is associated with rapid weight loss and improvements in sleep quality, daytime sleepiness, and the risk of OSA 6 months after surgery.
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