Cancer via Alexandros G.Sfakianakis on Inoreader

Source:  Cancer via Alexandros G.Sfakianakis on Inoreader    Tag:  scid life expectancy
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Cancer via Alexandros G.Sfakianakis on Inoreader

Treatment-Induced Metastasis
12:46:47 AM Ebos, J. M. L.
The arsenal of treatments for most cancers fit broadly into the categories of surgery, chemotherapy, radiation, and targeted therapy. All represent proven and successful strategies, yet each can trigger local (tumor) and systemic (host) processes that elicit unwanted, often opposing, influences on cancer growth. Under certain conditions, nearly all cancer treatments can facilitate metastatic spread, often in parallel (and sometimes in clear contrast) with tumor reducing benefits. The paradox of treatment-induced metastasis (TIM) is not new. Supporting preclinical studies span decades, but are often overlooked. With recent evidence of prometastatic effects following treatment with targeted agents blocking the tumor microenvironment, a closer inspection of this literature is warranted. The TIM phenomena may diminish the impact of effective therapies and play a critical role in eventual resistance. Alternatively, it may simply exemplify the gap between animal and human studies, and therefore have little impact for patient disease and treatment. This review will focus on the preclinical model systems used to evaluate TIM and explore the mechanisms that influence overall treatment efficacy. Understanding the role of TIM in established and emerging drug treatment strategies may help provide rationales for future drug combination approaches with antimetastatic agents to improve outcomes and reduce resistance. Cancer Res; 75(17); 1-9. ©2015 AACR.


Anti-CD20 therapy acts via Fc{gamma}RIIIA to diminish responsiveness of human natural killer cells
12:46:47 AM Capuano, C., Romanelli, M., Pighi, C., Cimino, G., Rago, A., Molfetta, R., Paolini, R., Santoni, A., Galandrini, R.
Natural killer (NK) immune cells mediate antibody-dependent cellular cytotoxicity (ADCC) by aggregating Fc?RIIIA/CD16, contributing significantly to the therapeutic effect of CD20 monoclonal antibodies (mAb). In this study, we show that CD16 ligation on primary human NK cells by the anti-CD20 mAb rituximab or ofatumumab stably impairs the spontaneous cytotoxic response attributable to cross-tolerance of several unrelated NK activating receptors (including NKG2D, DNAM-1, NKp46 and 2B4). Similar effects were obtained from NK cells isolated from chronic lymphocytic leukemia (CLL) patients in an autologous setting. NK cells rendered hyporesponsive in this manner were deficient in the ability of these cross-tolerized receptors to phosphorylate effector signaling molecules critical for NK cytotoxicity, including SLP-76, PLC?2 and Vav1. These effects were associated with long-lasting recruitment of the tyrosine phosphatase SHP-1 to the CD16 receptor complex. Notably, pharmacological inhibition of SHP-1 with sodium stibogluconate counteracted CD20 mAb-induced NK hyporesponsiveness, unveiling an unrecognized role for CD16 as a bifunctional receptor capable of engendering long-lasting NK cell inhibitory signals. Our work defines a novel mechanism of immune exhaustion induced by CD20 mAb in human NK cells, with potentially negative implications in CD20 mAb-treated patients where NK cells are partly responsible for clinical efficacy. -


HPV Persistence Predicts Poor Prognosis in Head/Neck Cancer
Thursday, July 30, 2015 9:53 PM Oral Cancer Foundation News Team - A
Source: www.medscape.com Author: Roxanne Nelson, RN, BSN   Among patients with human papillomavirus-positive oropharyngeal cancer (HPV-OPC), persistence of HPV following treatment is associated with a poorer prognosis. Results of a new study show that the persistence of HPV16 DNA, detected in oral rinses after treatment has ended, may be predictive of disease recurrence. In a [.]


Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth.
Thursday, July 30, 2015 9:49 PM Laura D. Hover, Christian D. Young, Neil E. Bhola, Andrew J. Wilson, Dineo Khabele, Charles C. Hong, Harold L. Moses, Philip Owens
. Bone morphogenetic protein (BMP) ligands are overexpressed in ovarian cancer.. BMP receptors increased expression correlate with poor progression-free-survival (PFS).. Small molecule BMP receptor inhibitor DMH1 reduces ovarian cancer cell growth.. DMH1 enhances effect of cisplatin chemotherapy and in cisplatin resistant cell lines.


Dietary flavonoid fisetin binds to ?-tubulin and disrupts microtubule dynamics in prostate cancer cells
Thursday, July 30, 2015 9:49 PM Eiman Mukhtar, Vaqar Mustafa Adhami, Mario Sechi, Hasan Mukhtar
. Fisetin enhances tubulin polymerization and increases ?-tubulin acetylation. Fisetin renders cells resistant to cold-induced microtubule depolymerization. Fisetin increases expression of MAP-2 and MAP-4. Fisetin decreases expression of NudC. Fisetin arrests cells in the G2/M phase of cell cycle. Fisetin inhibits cells proliferation, invasion and migration. Fisetin inhibits the viability, colony formation and decreases expression of P-gp in multidrug-resistant cancer cell line NCI/ADR-RES


Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth.
Thursday, July 30, 2015 9:13 PM Laura D. Hover, Christian D. Young, Neil E. Bhola, Andrew J. Wilson, Dineo Khabele, Charles C. Hong, Harold L. Moses, Philip Owens
. Bone morphogenetic protein (BMP) ligands are overexpressed in ovarian cancer.. BMP receptors increased expression correlate with poor progression-free-survival (PFS).. Small molecule BMP receptor inhibitor DMH1 reduces ovarian cancer cell growth.. DMH1 enhances effect of cisplatin chemotherapy and in cisplatin resistant cell lines.


Dietary flavonoid fisetin binds to ?-tubulin and disrupts microtubule dynamics in prostate cancer cells
Thursday, July 30, 2015 9:13 PM Eiman Mukhtar, Vaqar Mustafa Adhami, Mario Sechi, Hasan Mukhtar
. Fisetin enhances tubulin polymerization and increases ?-tubulin acetylation. Fisetin renders cells resistant to cold-induced microtubule depolymerization. Fisetin increases expression of MAP-2 and MAP-4. Fisetin decreases expression of NudC. Fisetin arrests cells in the G2/M phase of cell cycle. Fisetin inhibits cells proliferation, invasion and migration. Fisetin inhibits the viability, colony formation and decreases expression of P-gp in multidrug-resistant cancer cell line NCI/ADR-RES


Stratification of resectable lung adenocarcinoma by molecular and pathological risk estimators
Thursday, July 30, 2015 8:40 PM Emad Rakha, Maria J. Pajares, Marius Ilie, Ruben Pio, Jose Echeveste, Elisha Hughes, Irshad Soomro, Elodie Long, Miguel A. Idoate, Susanne Wagner, Jerry S. Lanchbury, David R. Baldwin, Paul Hofman, Luis M. Montuenga
Mortality in early stage, resectable lung cancer is sufficiently high to warrant consideration of post-surgical treatment. Novel markers to stratify resectable lung cancer patients may help with the selection of treatment to improve outcome.


Neoplastic transformation of porcine mammary epithelial cells in vitro and tumor formation in vivo
Thursday, July 30, 2015 8:30 PM A. Rowson-Hodel
Background: The mammary glands of pigs share many functional and morphological similarities with the breasts of humans, raising the potential of their utility for research into the mechanisms underlying normal mammary function and breast carcinogenesis. Here we sought to establish a model for the efficient manipulation and transformation of porcine mammary epithelial cells (pMEC) in vitro and tumor growth in vivo. Methods: We utilized a vector encoding the red florescent protein tdTomato to transduce populations of pMEC from Yorkshire -Hampshire crossbred female pigs in vitro and in vivo. Populations of primary pMEC were then separated by FACS using markers to distinguish epithelial cells (CD140a-) from stromal cells (CD140a+), with or without further enrichment for basal and luminal progenitor cells (CD49f+). These separated pMEC populations were transduced by lentivirus encoding murine polyomavirus T antigens (Tag) and tdTomato and engrafted to orthotopic or ectopic sites in immunodeficient NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice. Results: We demonstrated that lentivirus effectively transduces pMEC in vitro and in vivo. We further established that lentivirus can be used for oncogenic-transformation of pMEC ex vivo for generating mammary tumors in vivo. Oncogenic transformation was confirmed in vitro by anchorage-independent growth, increased cell proliferation, and expression of CDKN2A, cyclin A2 and p53 alongside decreased phosphorylation of Rb. Moreover, Tag-transformed CD140a- and CD140a-CD49f?+?pMECs developed site-specific tumors of differing histopathologies in vivo. Conclusions: Herein we establish a model for the transduction and oncogenic transformation of pMEC. This is the first report describing a porcine model of mammary epithelial cell tumorigenesis that can be applied to the study of human breast cancers.


Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial) - a randomized, multidisciplinary, multinational phase III trial
Thursday, July 30, 2015 8:30 PM Alexander Stein
Background: Despite complete resection, disease-free survival (DFS) of patients with cholangiocarcinoma (CCA) is less than 65 % after one year and not more than 35 % after three years. For muscle invasive gallbladder carcinoma (GBCA), prognosis is even worse, with an overall survival (OS) of only 30 % after three years. Thus, evaluation of adjuvant chemotherapy in biliary tract cancer in a large randomized trial is warranted.Methods/DesignACTICCA-1 is a randomized, multidisciplinary, multinational phase III investigator initiated trial. With respect to data obtained in the ABC-02 trial, we selected the combination of gemcitabine and cisplatin for 24 weeks as investigational treatment. Based on adjuvant trials in pancreatic cancer with comparable postoperative recovery time, inclusion of patients within a maximum interval of 16 weeks between surgery and start of chemotherapy was stipulated. Due to the different prognosis and treatment susceptibility of muscle invasive carcinoma, two separate cohorts (CCA and GBCA) were included to capture the potentially different treatment effects. Randomization is stratified for lymph node status for both cohorts and localization for CCA. The primary endpoint is DFS and secondary endpoints include OS, safety and tolerability of chemotherapy, quality of life, and patterns of disease recurrence. For CCA, adjuvant chemotherapy should increase DFS 24 months post-surgery from 40 to 55 % to be considered relevant. With a power of 80 % and a significance level of 5 %, 271 evaluable study patients have to be followed for 24-28 months to observe 166 events. For GBCA, chemotherapy should increase DFS 24 months post-surgery from 35 to 55 % to be of relevance; thus, 154 evaluable study patients have to be monitored for 24-28 months to observe 90 events. In both cohorts, randomization will be 1:1 with chemotherapy for 24 weeks and imaging every twelve weeks. In 2014, the study was initiated in Germany and in The Netherlands (funded by the Deutsche Krebshilfe, the Dutch Cancer Society, and supported by medac GmbH). Sites in Australia, Denmark, and the United Kingdom (funded by Cancer Research UK) are joining 2015.Trial registrationThe study is registered with ClinicalTrials.gov (NCT02170090) and the European Clinical Trials Database (2012-005078-70). Registration date is 06/18/2014.


Adenosine A2b receptor promotes progression of human oral cancer
Thursday, July 30, 2015 8:30 PM Hiroki Kasama
Background: Adenosine A2b receptor (ADORA2B) encodes an adenosine receptor that is a member of the G protein-coupled receptor superfamily. This integral membrane protein stimulates adenylate cyclase activity in the presence of adenosine. Little is known about the relevance of ADORA2B to human malignancy including oral squamous cell carcinoma (OSCC). We aimed to characterize the expression state and function of ADORA2B in OSCC. Methods: The ADORA2B expression levels in nine OSCC-derived cells were analyzed by quantitative reverse transcriptase-polymerase chain reaction and immunoblotting analyses. Using an ADORA2B knockdown model, we assessed cellular proliferation and expression of hypoxia-inducible factor1? (HIF-1?). We examined the adenosine receptor expression profile under both normoxic and hypoxic conditions in the OSCC-derived cells. In addition to in vitro data, the clinical correlation between the ADORA2B expression levels in primary OSCCs (n?=?100 patients) and the clinicopathological status by immunohistochemistry (IHC) also was evaluated. Results: ADORA2B mRNA and protein were up-regulated significantly (p?<?0.05) in seven OSCC-derived cells compared with human normal oral keratinocytes. Suppression of ADORA2B expression with shRNA significantly (p?<?0.05) inhibited cellular proliferation compared with the control cells. HIF-1? also was down-regulated in ADORA2B knockdown OSCC cells. During hypoxia, ADORA2B expression was induced significantly (p?<?0.05) in the mRNA and protein after 24 hours of incubation in OSCC-derived cells. IHC showed that ADORA2B expression in primary OSCCs was significantly (p?<?0.05) greater than in the normal oral counterparts and that ADORA2B-positive OSCCs were correlated closely (p?<?0.05) with tumoral size. Conclusion: Our results suggested that ADORA2B controls cellular proliferation via HIF-1? activation, indicating that ADORA2B may be a key regulator of tumoral progression in OSCCs.


A novel cytosporone 3-Heptyl-4,6-dihydroxy-3H-isobenzofuran-1-one: synthesis; toxicological, apoptotic and immunomodulatory properties; and potentiation of mutagenic damage
Thursday, July 30, 2015 8:30 PM Rodrigo Oliveira
Background: A large number of studies are attempting to identify alternative products from natural sources or synthesized compounds that effectively interact with cancer cells without causing adverse effects on healthy cells. Resorcinolic lipids are a class of bioactive compounds that possess anticancer activity and are able to interact with the lipid bilayer. Therefore, the objective of this study was to synthesize a novel resorcinolic lipid and test its biological proprieties. Methods: We aimed to synthesize a novel resorcinolic lipid belonging to the class of cytosporones, AMS049 (3-Heptyl-4,6-dihydroxy-3H-isobenzofuran-1-one) and to evaluate the toxicity of two concentrations of this lipid (7.5 and 10 mg/kg) by determining its genotoxic, mutagenic, immunomodulatory, and apoptotic effects, as well as any biochemical and histopathological alterations in mice treated with cyclophosphamide. The results were analyzed by ANOVA followed by the Tukey test A . level of significance of p?<?0.05 was adopted. Results: The new cytosporone AMS049 was synthesized in only three steps and in satisfactory yields. The results indicate that the compound is neither genotoxic nor mutagenic and does not alter biochemical parameters. The histological alterations observed in the liver and kidneys did not compromise the function of these organs. Histology of the spleen suggested immunomodulation, although no changes were observed in splenic phagocytosis or differential blood cell count. The results also show that AMS049 potentiates the mutagenic effect of the chemotherapy drug cyclophosphamide and that the combination induces apoptosis. Conclusion: These facts indicate a potential therapeutic application of this novel cytosporone as an important chemotherapeutic adjuvant.


XAB2 tagSNPs contribute to non-small cell lung cancer susceptibility in Chinese population
Thursday, July 30, 2015 8:30 PM Na Pei
Background: XPA-binding protein 2 (XAB2) interacts with Cockayne syndrome complementation group A (CSA), group B (CSB) and RNA polymerase II to initiate nucleotide excision repair. This study aims to evaluate the association of XAB2 genetic variants with the risk of non-small cell lung cancer (NSCLC) using a tagging approach. Methods: A hospital-based case-control study was conducted in 470 patients with NSCLC and 470 controls in Chinese population. Totally, 5 tag single nucleotide polymorphisms (SNPs) in XAB2 gene were selected by Haploview software using Hapmap database. Genotyping was performed using iPlex Gold Genotyping Asssy and Sequenom MassArray. Unconditional logistic regression was conducted to estimate odd ratios (ORs) and 95 % confidence intervals (95 % CI). Results: Unconditional logistic regression analysis showed that the XAB2 genotype with rs794078 AA or at least one rs4134816 C allele were associated with the decreased risk of NSCLC with OR (95 % CI) of 0.12 (0.03-0.54) and 0.46 (0.26-0.84). When stratified by gender, we found that the subjects carrying rs4134816 CC or CT genotype had a decreased risk for developing NSCLC among males with OR (95 % CI) of 0.39 (0.18-0.82), but not among females. In age stratification analysis, we found that younger subjects (age???60) with at least one C allele had a decreased risk of NSCLC with OR (95 % CI) of 0.35 (0.17-0.74), but older subjects didn't. We didn't find that XAB2 4134816 C?>?T variant effect on the risk of NSCLC when stratified by smoking status. The environmental factors, such as age, sex and smoking had no effect on the risk of NSCLC related to XAB2 genotypes at other polymorphic sites. Conclusions: The XAB2 tagSNPs (rs794078 and rs4134816) were significantly associated with the risk of NSCLC in Chinese population, which supports the XAB2 plays a significant role in the development of NSCLC.


Cancer patients lose faith in healthcare system if referred late by GP
Thursday, July 30, 2015 7:27 PM
If it takes more than three trips to the GP to be referred for cancer tests, patients are more likely to be dissatisfied with their overall care, eroding confidence in the doctors and nurses who go on to treat and monitor them. These worrying levels of...


The impact of positive peritoneal cytology on prognosis in patients with cervical cancer: a meta-analysis
Thursday, July 30, 2015 6:51 PM Sang-Hee Yoon

The impact of positive peritoneal cytology on prognosis in patients with cervical cancer: a meta-analysis

British Journal of Cancer advance online publication, July 30 2015. doi:10.1038/bjc.2015.266

Authors: Sang-Hee Yoon, Soo-Nyung Kim, Seung-Hyuk Shim, Ji-Young Lee, Sun-Joo Lee, In-Kyeong Oh, Hyeon-Jeong Kim & Soon-Beom Kang



Cancer serum biomarkers based on aberrant post-translational modifications of glycoproteins: clinical value and discovery strategies
Thursday, July 30, 2015 6:49 PM
Publication date: Available online 30 July 2015
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): M. Luísa S. Silva
Due to the increase in life expectancy in the last decades, as well as changes in life style, cancer has become one of the most common diseases both in developed and developing countries. Early detection remains the most promising approach to improve long-term survival of cancer patients and this may be achieved by efficient screening of biomarkers in biological fluids. Great efforts have been made to identify specific alterations during oncogenesis. Changes at the cellular glycosylation profiles are among such alterations. The "glycosylation machinery" of cells is affected by malignant transformation due to the altered expression of glycogens, leading to changes in glycan biosynthesis and diversity. Alterations in the post-translational modifications of proteins that occur in cancer result in the expression of antigenically distinct glycoproteins. Therefore, these aberrant and cancer-specific glycoproteins and the autoantibodies that are produced in response to their presence constitute targets for cancer biomarkers' search. Different strategies have been implemented for the discovery of cancer glycobiomarkers and are herein reviewed, along with their potentialities and limitations. Practical issues related with serum analysis are also addressed, as well as the challenges that this area faces in the near future.



Secondary Data Analytics of Aquaporin Expression Levels in Glioblastoma Stem-Like Cells
Thursday, July 30, 2015 6:45 PM Raphael D. Isokpehi
Glioblastoma is the most common brain tumor in adults in which recurrence has been attributed to the presence of cancer stem cells in a hypoxic microenvironment. On the basis of tumor formation in vivo and growth type in vitro, two published microarray gene expression profiling studies grouped nine glioblastoma stem-like (GS) cell lines into one of two groups: full (GSf) or restricted (GSr) stem-like phenotypes. Aquaporin-1 (AQP1) and aquaporin-4 (AQP4) are water transport proteins that are highly expressed in primary glial-derived tumors. However, the expression levels of AQP1 and AQP4 have not been previously described in a panel of 92 glioma samples. Therefore, we designed secondary data analytics methods to determine the expression levels of AQP1 and AQP4 in GS cell lines and glioblastoma neurospheres. Our investigation also included a total of 2,566 expression levels from 28 Affymetrix microarray probe sets encoding 13 human aquaporins (AQP0-AQP12); CXCR4 (the receptor for stromal cell derived factor-1 SDF-1, a potential glioma stem cell therapeutic target); and PROM1 (gene encoding CD133, the widely used glioma stem cell marker). Interactive visual representation designs for integrating phenotypic features and expression levels revealed that inverse expression levels of AQP1 and AQP4 correlate with distinct phenotypes in a set of cell lines grouped into full and restricted stem-like phenotypes. Discriminant function analysis further revealed that AQP1 and AQP4 expression are better predictors for tumor formation and growth types in glioblastoma stem-like cells than are CXCR4 and PROM1. Future investigations are needed to characterize the molecular mechanisms for inverse expression levels of AQP1 and AQP4 in the glioblastoma stem-like neurospheres.


Analysis of Epidermal Growth Factor Receptor Mutations in Serum among Japanese Patients Treated with First-Line Erlotinib for Advanced Non-Small-Cell Lung Cancer
Thursday, July 30, 2015 3:58 PM Makoto Nishio, Koichi Goto, Kenichi Chikamori, Toyoaki Hida, Nobuyuki Katakami, Makoto Maemondo, Norihisa Ohishi, Tomohide Tamura
Analysis of serum to detect EGFR mutations may be an alternative to using tumor tissue. Scorpion-ARMS was used to detect serum EGFR mutations in the single-arm Japanese JO22903 erlotinib study. Serum EGFR mutations (exon 19 deletions or L858R) were detected in 26.3% of patients analyzed; agreement between tumor and serum results was 96.2%. As sensitivity was low, further validation of serum-based EGFR analysis is needed.


Let-7a-3 hypomethylation is associated with favorable/intermediate karyotypes but not with survival in acute myeloid leukemia
Thursday, July 30, 2015 3:42 PM

Abstract

Aberrant methylation of let-7a-3 promoter has been observed in various malignancies. However, the clinical relevance of let-7a-3 methylation remains poorly known in acute myeloid leukemia (AML). This study was to investigate the let-7a-3 methylation status and to explore its clinical significance in AML. let-7a-3 promoter was significantly hypomethylated in AML patients compared to controls (median 4.51 vs 0.49) (P?=?0.0003). Receiver operating characteristic curve (ROC) analysis discriminated all patients or cytogenetically normal patients from controls with an areas under the ROC curve (AUC) of 0.737 or 0.783, respectively (P?<?0.001). Patients with favorable/intermediate karyotypes had significantly higher let-7a-3 unmethylation than controls. Patients with DNMT3A mutations had a trend of high level of let-7a-3 unmethylation than did those with wild-type DNMT3A (median 6.76 vs 3.66, P?=?0.096). There was no significant difference in overall survival between patients with and without hypomethylated let-7a-3 (median 12 vs 5 months, P?=?0.103). No correlation was observed between the level of let-7a-3 expression and let-7a-3 unmethylation in AML samples (R?=?0.197, P?=?0.150). However, the level of let-7a-3 expression was increased in a dose-dependent manner in THP-1 line treated with 5-aza-dC, while the methylation density of let-7a-3 promoter decreased with 5-aza-dC dose. Our findings suggest that let-7a-3 hypomethylation is associated with favorable and intermediate karyotypes but not a prognostic predictor for AML patients. Let-7a-3 expression may be partially regulated by promoter methylation.



Down-regulation of Sphk2 suppresses bladder cancer progression
Thursday, July 30, 2015 3:42 PM

Abstract

Bladder cancer is the second most common urological malignancy around the world and is by far the most frequent urological malignancy in China. The abnormal expression of sphingosine kinase 2 (SphK2) is associated with tumor progression and a poor patient survival rate, however, the effect of SphK2 on the bladder cancer cells remains unclear. The aim of the paper was to study the expression of SphK2 in bladder cancer and the role of SphK2 on the cell proliferation, metastasis, and apoptosis in bladder cancer in vitro. Our results showed that SphK2 is up-regulated in bladder cancer tissues compared with the corresponding adjacent non-neoplastic tissues, and the expression level of SphK2 was significantly higher in human bladder cancer cells in comparison with normal bladder epithelial cells. Silencing of SphK2 could inhibit the proliferation ability of T24 cells in vitro. In addition, SphK2 knockdown could induce a significant increase in the number of apoptotic cells. Furthermore, the transwell assay also showed significant cell migration inhibition in SphK2 siRNA transfectant compared with cell lines transfected with NC. Thus, this study suggested that SphK2 inhibition may provide a promising treatment for bladder cancer patients.



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