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  1 / 1999174 MEDLINE  
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[PMID]: 25976292
[Au] Autor:Loh ML; Tasian SK; Rabin KR; Brown P; Magoon D; Reid JM; Chen X; Ahern CH; Weigel BJ; Blaney SM
[Ad] Address:Department of Pediatrics, UCSF Benioff Children's Hospital, San Francisco, California....
[Ti] Title:A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: A Children's Oncology Group phase 1 consortium study (ADVL1011).
[So] Source:Pediatr Blood Cancer;62(10):1717-24, 2015 Oct.
[Is] ISSN:1545-5017
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: Ruxolitinib, an orally bioavailable JAK1/JAK2 inhibitor, may treat cancers with CRLF2 and/or JAK pathway mutations. PROCEDURE: A phase 1 trial of ruxolitinib was performed to determine the maximum tolerated or recommended phase 2 dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) in children with recurrent/refractory solid tumors (STs). Ruxolitinib was administered twice daily (BID) in 28-day cycles at five dose levels (15, 21, 29, 39, and 50 mg/m(2) /dose). PK and PD studies were performed during cycle 1. Toxicity, preliminary efficacy, and PK/PD were also assessed in children with relapsed/refractory hematologic malignancies (HMs). RESULTS: Forty-nine patients were enrolled, 28 with STs (dose escalation cohort) and 21 with HMs. Ruxolitinib was well-tolerated with one DLT per cohort of six patients at dose levels (DLs) 2-5. One patient with an ST had grade 5 multi-organ failure at DL2. One patient each at DL3 and DL4 had a grade 4 neutropenia, and one patient at DL5 had a grade 4 creatinine phosphokinase elevation. No objective responses were observed in patients with STs. One patient with polycythemia vera achieved a partial response and received 18 cycles of ruxolitinib. The PK of ruxolitinib were similar to that in adults. Partial inhibition of phosphorylated JAK2, STAT5, and S6 was observed in in vitro plasma inhibitory activity PD assay. CONCLUSION: Ruxolitinib was well tolerated in children with refractory cancer. The recommended phase 2 dose for continuous BID oral administration is 50 mg/m(2) /dose. Subsequent evaluation of ruxolitinib in combination with cytotoxic chemotherapy in children, adolescents, and young adults with JAK-mutant leukemias is planned. Pediatr Blood Cancer 2015;62:1717-1724. © 2015 Wiley Periodicals, Inc.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1508
[Cu] Class update date: 150822
[Lr] Last revision date:150822
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1002/pbc.25575

  2 / 1999174 MEDLINE  
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[PMID]: 26209458
[Au] Autor:Cauley CE; Pitman MB; Zhou J; Perkins J; Kuleman B; Liss AS; Fernandez-Del Castillo C; Warshaw AL; Lillemoe KD; Thayer SP
[Ad] Address:Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Electronic address: ccauley@partners.org....
[Ti] Title:Circulating Epithelial Cells in Patients with Pancreatic Lesions: Clinical and Pathologic Findings.
[So] Source:J Am Coll Surg;221(3):699-707, 2015 Sep.
[Is] ISSN:1879-1190
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: Circulating epithelial cell (CEC) isolation has provided diagnostic and prognostic information for a variety of cancers, previously supporting their identity as circulating tumor cells in the literature. However, we report CEC findings in patients with benign, premalignant, and malignant pancreatic lesions using a size-selective filtration device. STUDY DESIGN: Peripheral blood samples were drawn from patients found to have pancreatic lesions on preoperative imaging at a surgical clinic. Blood was filtered using ScreenCell devices, which were evaluated microscopically by a pancreatic cytopathologist. Pathologic data and clinical outcomes of these patients were obtained from medical records during a 1-year follow-up period. RESULTS: Nine healthy volunteers formed the control group and were found to be negative for CECs. There were 179 patients with pancreatic lesions that formed the study cohort. Circulating epithelial cells were morphologically similar in patients with a variety of pancreatic lesions. Specifically, CECs were identified in 51 of 105 pancreatic ductal adenocarcinomas (49%), 7 of 11 neuroendocrine tumors (64%), 13 of 21 intraductal papillary mucinous neoplasms (62%), and 6 of 13 patients with chronic pancreatitis. Rates of CEC identification were similar in patients with benign, premalignant, and malignant lesions (p = 0.41). In addition, CEC findings in pancreatic ductal adenocarcinoma patients were not associated with poor prognosis. CONCLUSIONS: Although CECs were not identified in healthy volunteers, they were identified in patients with benign, premalignant, and malignant pancreatic lesions. The presence of CECs in patients presenting with pancreatic lesions is neither diagnostic of malignancy nor prognostic for patients with pancreatic ductal adenocarcinoma.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1508
[Cu] Class update date: 150822
[Lr] Last revision date:150822
[Js] Journal subset:AIM; IM
[St] Status:In-Data-Review

  3 / 1999174 MEDLINE  
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[PMID]: 26106858
[Au] Autor:Melo SA; Luecke LB; Kahlert C; Fernandez AF; Gammon ST; Kaye J; LeBleu VS; Mittendorf EA; Weitz J; Rahbari N; Reissfelder C; Pilarsky C; Fraga MF; Piwnica-Worms D; Kalluri R
[Ad] Address:Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA....
[Ti] Title:Glypican-1 identifies cancer exosomes and detects early pancreatic cancer.
[So] Source:Nature;523(7559):177-82, 2015 Jul 9.
[Is] ISSN:1476-4687
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer-cell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer-cell-derived exosomes. GPC1(+) circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of patients and mice with cancer. GPC1(+) crExos were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer. Levels of GPC1(+) crExos correlate with tumour burden and the survival of pre- and post-surgical patients. GPC1(+) crExos from patients and from mice with spontaneous pancreatic tumours carry specific KRAS mutations, and reliably detect pancreatic intraepithelial lesions in mice despite negative signals by magnetic resonance imaging. GPC1(+) crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy.
[Mh] MeSH terms primary: Exosomes/metabolism
Glypicans/diagnostic use
Pancreatic Neoplasms/diagnosis
[Mh] MeSH terms secundary: Animals
Biological Markers/blood
Cell Line, Tumor
Exosomes/genetics
Female
Glypicans/blood
Glypicans/metabolism
HCT116 Cells
Humans
MCF-7 Cells
Male
Mice
NIH 3T3 Cells
Pancreatic Neoplasms/blood
Pancreatic Neoplasms/pathology
Proto-Oncogene Proteins/metabolism
ras Proteins/metabolism
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Biological Markers); 0 (Glypicans); 0 (KRAS protein, human); 0 (Proto-Oncogene Proteins); EC 3.6.5.2 (ras Proteins)
[Em] Entry month:1507
[Cu] Class update date: 150822
[Lr] Last revision date:150822
[Js] Journal subset:IM
[Da] Date of entry for processing:150709
[St] Status:MEDLINE
[do] DOI:10.1038/nature14581

  4 / 1999174 MEDLINE  
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[PMID]: 25524243
[Au] Autor:Tsai HT; Keating NL; Van Den Eeden SK; Haque R; Cassidy-Bushrow AE; Ulcickas Yood M; Smith MR; Potosky AL
[Ad] Address:Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC. Electronic address: ht92@georgetown.edu....
[Ti] Title:Risk of diabetes among patients receiving primary androgen deprivation therapy for clinically localized prostate cancer.
[So] Source:J Urol;193(6):1956-62, 2015 Jun.
[Is] ISSN:1527-3792
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:PURPOSE: Androgen deprivation therapy may increase diabetes risk. As the benefits of primary androgen deprivation therapy for localized prostate cancer are controversial, and most prostate cancer survivors are of advanced age with comorbidities, it is important to determine if primary androgen deprivation therapy increases the risk of diabetes and to determine the susceptibility factors. MATERIALS AND METHODS: We conducted a retrospective cohort study of 12,191 men diagnosed with incident localized prostate cancer during 1995 to 2008, age 35 to 100 years, and without diabetes or receipt of prostatectomy or radiation 1 year after diagnosis. Patients were enrolled in 1 of 3 managed health plans and followed through 2010. Primary androgen deprivation therapy was defined as androgen deprivation therapy within 1 year after diagnosis. Incident diabetes was ascertained using inpatient and outpatient diagnosis codes, diabetes medications and hemoglobin A1c values. We estimated primary androgen deprivation therapy associated diabetes risk using Cox proportional hazard models in conventional and propensity score analyses. RESULTS: Diabetes developed in 1,203 (9.9%) patients during followup (median 4.8 years) with incidence rates of 2.5 and 1.6 events per 100 person-years in the primary androgen deprivation therapy and nonprimary androgen deprivation therapy groups, respectively. Primary androgen deprivation therapy was associated with a 1.61-fold increased diabetes risk (95% CI 1.38-1.88). The number needed to harm was 29. The association was stronger in men age 70 or younger than in older men (HR 2.25 vs 1.40, p value for interaction=0.008). CONCLUSIONS: Primary androgen deprivation therapy may increase diabetes risk by 60% and should be used with caution when managing localized prostate cancer. Because of the consistent association between androgen deprivation therapy and greater diabetes risk across disease states, we recommend routine screening and lifestyle interventions to reduce the risk of diabetes in men receiving androgen deprivation therapy.
[Mh] MeSH terms primary: Androgen Antagonists/adverse effects
Diabetes Mellitus/chemically induced
Diabetes Mellitus/epidemiology
Gonadotropin-Releasing Hormone/analogs & derivatives
Gonadotropin-Releasing Hormone/antagonists & inhibitors
Prostatic Neoplasms/drug therapy
[Mh] MeSH terms secundary: Adult
Aged
Aged, 80 and over
Cohort Studies
Humans
Male
Middle Aged
Retrospective Studies
Risk
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Name of substance:0 (Androgen Antagonists); 33515-09-2 (Gonadotropin-Releasing Hormone)
[Em] Entry month:1507
[Cu] Class update date: 150822
[Lr] Last revision date:150822
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:150519
[St] Status:MEDLINE

  5 / 1999174 MEDLINE  
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[PMID]: 25965353
[Au] Autor:Pickhardt PJ
[Ad] Address:Department of Radiology, University of Wisconsin School of Medicine & Public Health, Madison, WI.
[Ti] Title:Colorectal carcinoma: what should the oncologist recommend for screening?
[So] Source:Semin Oncol;42(3):359-61, 2015 Jun.
[Is] ISSN:1532-8708
[Cp] Country of publication:United States
[La] Language:eng
[Mh] MeSH terms primary: Colorectal Neoplasms/diagnosis
[Mh] MeSH terms secundary: Colonoscopy
Colorectal Neoplasms/prevention & control
Early Detection of Cancer
Humans
Medical Oncology
Sensitivity and Specificity
[Pt] Publication type:EDITORIAL; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Em] Entry month:1507
[Cu] Class update date: 150822
[Lr] Last revision date:150822
[Js] Journal subset:IM
[Da] Date of entry for processing:150513
[St] Status:MEDLINE

  6 / 1999174 MEDLINE  
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[PMID]: 25236485
[Au] Autor:Wani S; Das A; Rastogi A; Drahos J; Ricker W; Parsons R; Bansal A; Yen R; Hosford L; Jankowski M; Sharma P; Cook MB
[Ad] Address:Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Center, Aurora, Colorado; Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center, Denver, Colorado.
[Ti] Title:Endoscopic ultrasonography in esophageal cancer leads to improved survival rates: results from a population-based study.
[So] Source:Cancer;121(2):194-201, 2015 Jan 15.
[Is] ISSN:1097-0142
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: The advantages of endoscopic ultrasound (EUS) and computed tomography (CT)-positron emission tomography (PET) with respect to survival for esophageal cancer patients are unclear. This study aimed to assess the effects of EUS, CT-PET, and their combination on overall survival with respect to cases not receiving these procedures. METHODS: Patients who were ≥66 years old when diagnosed with esophageal cancer were identified in the Surveillance, Epidemiology, and End Results-Medicare linked database. Cases were split into 4 analytic groups: EUS only (n = 318), CT-PET only (n = 853), EUS+CT-PET (n = 189), and no EUS or CT-PET (n = 2439). Survival times were estimated with the Kaplan-Meier method and were compared with the log-rank test for each group versus the no EUS or CT-PET group. Multivariate Cox proportional hazards models were used to compare 1-, 3-, and 5-year survival rates. RESULTS: Kaplan-Meier analyses showed that EUS, CT-PET, and EUS+CT-PET patients had improved survival for all stages (with the exception of stage 0 disease) in comparison with patients undergoing no EUS or CT-PET. Receipt of EUS increased the likelihood of receiving endoscopic therapies, esophagectomy, and chemoradiation. Multivariate Cox proportional hazards models showed that receipt of EUS was a significant predictor of improved 1- (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.39-0.59; P < .0001), 3- (HR, 0.57; 95% CI, 0.48-0.66; P < .0001), and 5-year survival (HR, 0.59; 95% CI, 0.50-0.68). Similar results were noted when the results were stratified on the basis of histology and for the CT-PET and EUS+CT-PET groups. CONCLUSIONS: Receipt of either EUS or CT-PET alone in esophageal cancer patients was associated with improved 1-, 3-, and 5-year survival. Future studies should identify barriers to the dissemination of these staging modalities.
[Mh] MeSH terms primary: Endosonography
Esophageal Neoplasms/mortality
Esophageal Neoplasms/ultrasonography
Multimodal Imaging/methods
Positron-Emission Tomography
Tomography, X-Ray Computed
[Mh] MeSH terms secundary: Adenocarcinoma/mortality
Adenocarcinoma/ultrasonography
Adult
Aged
Carcinoma, Squamous Cell/mortality
Carcinoma, Squamous Cell/ultrasonography
Esophageal Neoplasms/diagnosis
Esophageal Neoplasms/pathology
Female
Humans
Kaplan-Meier Estimate
Male
Medicare
Middle Aged
Neoplasm Staging
Proportional Hazards Models
SEER Program
Sensitivity and Specificity
United States/epidemiology
[Pt] Publication type:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1503
[Cu] Class update date: 150822
[Lr] Last revision date:150822
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:150113
[St] Status:MEDLINE
[do] DOI:10.1002/cncr.29043

  7 / 1999174 MEDLINE  
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[PMID]: 25574959
[Au] Autor:Borges ÁH; Lundgren JD; Ridolfo A; Katlama C; Antunes F; Grzeszczuk A; Blaxhult A; Mitsura VM; Doroana M; Battegay M; Gargalianos P; Mocroft A; EuroSIDA in EuroCOORD
[Ad] Address:aCentre for Health & Infectious Diseases Research (CHIP), Department of Infectious Diseases and Rheumatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark bClinica delle Malattie Infettive, Ospedale L. Sacco, Milan, Italy cDept de Medicine Tropicale, Hopital de la Pitié-Salpêtriére, Paris, France dInstituto de Saúde Ambiental, Faculdade de Medicina de Lisboa eServiço de Doenças Infecciosas, Hospital de Santa Maria, Lisbon, Portugal fDepartment of Infectious Diseases, Wojewodzki Szpital Specjalistyczny, Bialystok, Poland gDepartment of Infectious Diseases, Södersjukhuset Venhälsan, Stockholm, Sweden hInfectious Diseases Department, Gomel State Medical University, Gomel, Belarus iDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland j1st Department of Internal Medicine, Athens General Hospital 'G. Gennimatas', Athens, Greece kDepartment of Infection and Population Health, University College London, London, UK. *Study group listed in the Acknowledgements section.
[Ti] Title:Thrombocytopenia is associated with an increased risk of cancer during treated HIV disease.
[So] Source:AIDS;28(17):2565-71, 2014 Nov 13.
[Is] ISSN:1473-5571
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:OBJECTIVE: To assess the relationship between platelet counts and risk of AIDS and non-AIDS-defining events. DESIGN: Prospective cohort. METHODS: EuroSIDA patients with at least one platelet count were followed from baseline (first platelet ≥ 1 January 2005) until last visit or death. Multivariate Poisson regression was used to assess the relationship between current platelet counts and the incidence of non-AIDS-defining (pancreatitis, end-stage liver/renal disease, cancer, cardiovascular disease) and AIDS-defining events. RESULTS: There were 62 898 person-years of follow-up (PYFU) among 12 279 patients, including 1168 non-AIDS-defining events [crude incidence 18.6/1000 PYFU, 95% confidence interval (CI) 17.5-19.6] and 735 AIDS-defining events (crude incidence 11.7/1000 PYFU, 95% CI 10.8-12.5). Patients with thrombocytopenia (platelet count ≤100 × 10/l) had a slightly increased incidence of AIDS-defining events [adjusted incidence rate ratio (aIRR) 1.42, 95% CI 1.07-1.86], when compared to those with platelet counts 101-200 × 10/l, whereas the incidence of non-AIDS-defining events was more than two-fold higher (aIRR 2.66, 95% CI 2.17-3.26). Among non-AIDS-defining events, the adjusted incidence of cancer (aIRR 2.20, 95% CI 1.61-3.01), but not cardiovascular disease (aIRR 0.66, 95% CI 0.32-1.34), was significantly higher in patients with thrombocytopenia. The association between thrombocytopenia and cancer remained unaltered in sensitivity analyses requiring repeated platelet counts to confirm thrombocytopenia and lagging platelets by 1 year prior to clinical events. CONCLUSION: Patients with thrombocytopenia had increased incidence of AIDS-defining and non-AIDS-defining events, but the association with the latter, in particular cancer, was stronger. Future studies should investigate whether the pathophysiological processes underlying thrombocytopenia are associated with the development of cancer during treated HIV disease.
[Mh] MeSH terms primary: HIV Infections/complications
HIV Infections/drug therapy
Neoplasms/epidemiology
Thrombocytopenia/complications
[Mh] MeSH terms secundary: Adolescent
Adult
Aged
Cohort Studies
Female
Follow-Up Studies
Humans
Incidence
Male
Middle Aged
Prospective Studies
Risk Assessment
Young Adult
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1507
[Cu] Class update date: 150823
[Lr] Last revision date:150823
[Js] Journal subset:IM; X
[Da] Date of entry for processing:150110
[St] Status:MEDLINE
[do] DOI:10.1097/QAD.0000000000000433

  8 / 1999174 MEDLINE  
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[PMID]: 25491297
[Au] Autor:Asnaghi L; Alkatan H; Mahale A; Othman M; Alwadani S; Al-Hussain H; Jastaneiah S; Yu W; Maktabi A; Edward DP; Eberhart CG
[Ad] Address:Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States....
[Ti] Title:Identification of multiple DNA copy number alterations including frequent 8p11.22 amplification in conjunctival squamous cell carcinoma.
[So] Source:Invest Ophthalmol Vis Sci;55(12):8604-13, 2014 Dec.
[Is] ISSN:1552-5783
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:PURPOSE: Little is known about the molecular alterations that drive formation and growth of conjunctival squamous cell carcinoma (cSCC). We therefore sought to identify genetic changes that could be used as diagnostic markers or therapeutic targets. METHODS: The DNA extracted from 10 snap-frozen cSCC tumor specimens and 2 in situ carcinomas was analyzed using array-based comparative genomic hybridization (aCGH), and further examined with NanoString and quantitative PCR. RESULTS: The number of regions of DNA loss ranged from 1 to 23 per tumor, whereas gains and amplifications ranged from 1 to 15 per tumor. Most large regions of chromosomal gain and loss were confirmed by NanoString karyotype analysis. The commonest alteration was amplification of 8p11.22 in 9 tumors (75%), and quantitative PCR analysis revealed 100-fold or greater overexpression of ADAM3A mRNA from 8p11.22 locus. In addition, recurring losses were observed at 14q13.2 and 22q11.23, both lost in 5 (42%) of the 12 tumors, and at 12p13.31, lost in 4 (33%) of the 12 samples. Of the eight loci associated with the DNA damage repair syndrome xeroderma pigmentosum, three showed loss of at least one allele in our aCGH analysis, including XPA (9q22.33, one tumor), XPE/DDB2 (11p11.2, one tumor) and XPG/ERCC5 (13q33.1, three tumors). CONCLUSIONS: Conjunctival SCC contains a range of chromosomal alterations potentially important in tumor formation and growth. Amplification of 8p11.22 and overexpression of ADAM3A suggests a potential role for this protease. Our findings also suggest that defects in DNA repair loci are important in sporadic cSCC.
[Mh] MeSH terms primary: Carcinoma, Squamous Cell/genetics
Chromosomes, Human, Pair 8
Conjunctival Neoplasms/genetics
DNA Copy Number Variations/genetics
DNA, Neoplasm/genetics
[Mh] MeSH terms secundary: ADAM Proteins/metabolism
Aged
Carcinoma, Squamous Cell/metabolism
Comparative Genomic Hybridization/methods
Conjunctival Neoplasms/metabolism
Female
Gene Amplification
Genetic Markers/genetics
Humans
Male
Middle Aged
Real-Time Polymerase Chain Reaction
Tumor Markers, Biological/genetics
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (DNA, Neoplasm); 0 (Genetic Markers); 0 (Tumor Markers, Biological); EC 3.4.24.- (ADAM Proteins)
[Em] Entry month:1503
[Cu] Class update date: 150822
[Lr] Last revision date:150822
[Js] Journal subset:IM
[Da] Date of entry for processing:141231
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.14-14920

  9 / 1999174 MEDLINE  
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[PMID]: 25145330
[Au] Autor:Khatri N; Baradia D; Vhora I; Rathi M; Misra A
[Ad] Address:Pharmacy Department, The Maharaja Sayajirao University of Baroda, Kalabhavan, Vadodara, 390001, Gujarat, India.
[Ti] Title:Development and characterization of siRNA lipoplexes: Effect of different lipids, in vitro evaluation in cancerous cell lines and in vivo toxicity study.
[So] Source:AAPS PharmSciTech;15(6):1630-43, 2014 Dec.
[Is] ISSN:1530-9932
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Cationic liposomes have long been used as non-viral vectors for small interfering RNA (siRNA) delivery but are associated with high toxicity, less transfection efficiency, and in vivo instability. In this investigation, we have developed siRNA targeted to RRM1 that is responsible for development of resistance to gemcitabine in cancer cells. Effect of different lipid compositions has been evaluated on formation of stable and less toxic lipoplexes. Optimized cationic lipoplex (D2CH) system was comprised of dioleoyl-trimethylammoniumpropane (DOTAP), dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), hydrogenated soya phosphocholine (HSPC), cholesterol, and methoxy(polyethyleneglycol)2000-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (mPEG2000-DSPE). D2CH lipoplexes have shown particle size (147.5 ± 2.89 nm) and zeta potential (12.26 ± 0.54 mV) characteristics essential for their in vivo use. In vitro cytotoxicity study has shown low toxicity of developed lipoplexes as compared with lipofectamine-2000 up to N/P ratio as high as 7.5. Cell uptake studies and gene expression studies have confirmed intracellular availability of siRNA. In addition, developed lipoplexes also showed ~3 times less hemolytic potential as compared with DOTAP/DOPE lipoplexes at lipid concentration of 5 mg/mL. Lipoplexes also maintained particle size less than 200 nm on exposure to high electrolyte concentration and showed >70% siRNA retention in presence of serum showing siRNA protection conferred by lipoplexes. Furthermore, in vivo acute toxicity studies in mice showed that formulation was non-toxic up to a dosage of 0.75 mg of siRNA/kg as lipoplexes and 300 mg lipid/kg as blank liposomes indicating tolerability of lipoplexes at a dose much higher than required for therapeutic use. Promising results of this study warrant further investigation of developed siRNA lipoplexes for cancer treatment.
[Mh] MeSH terms primary: Genetic Therapy/methods
Lipids/chemistry
Neoplasms/therapy
RNA Interference
RNA, Small Interfering/metabolism
Transfection/methods
[Mh] MeSH terms secundary: Animals
Cell Line, Tumor
Cell Survival/drug effects
Female
Gene Expression Regulation, Neoplastic
Hemolysis/drug effects
Humans
Lipids/toxicity
Liposomes
Mice
Neoplasms/genetics
Neoplasms/metabolism
Neoplasms/pathology
Particle Size
RNA Stability
RNA, Small Interfering/blood
RNA, Small Interfering/chemistry
Tumor Suppressor Proteins/genetics
Tumor Suppressor Proteins/metabolism
[Pt] Publication type:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Lipids); 0 (Liposomes); 0 (RNA, Small Interfering); 0 (RRM1 protein, human); 0 (Tumor Suppressor Proteins)
[Em] Entry month:1507
[Cu] Class update date: 150822
[Lr] Last revision date:150822
[Js] Journal subset:IM
[Da] Date of entry for processing:141127
[St] Status:MEDLINE
[do] DOI:10.1208/s12249-014-0193-9

  10 / 1999174 MEDLINE  
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[PMID]: 25190496
[Au] Autor:Bottai G; Pasculli B; Calin GA; Santarpia L
[Ad] Address:IRCCS Clinical and Research Institute Humanitas, Experimental Therapeutics Unit , Via Manzoni 113 - 20089 Rozzano, Milan , Italy +39 02 8224 5173 ; +39 02 8224 5191 ; libero.santarpia@humanitasresearch.it ; liberosantarpia@yahoo.it.
[Ti] Title:Targeting the microRNA-regulating DNA damage/repair pathways in cancer.
[So] Source:Expert Opin Biol Ther;14(11):1667-83, 2014 Nov.
[Is] ISSN:1744-7682
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:INTRODUCTION: Maintenance of genome stability requires the integrity of the DNA repair machinery. DNA damage response (DDR) determines cell fate and regulates the expression of microRNAs (miRNAs), which in turn may also regulate important components of the DNA repair machinery. AREAS COVERED: In this review, we describe the bidirectional connection between miRNAs and DDR and their link with important biological functions such as, DNA repair, cell cycle and apoptosis in cancer. Furthermore, we highlight the potential implications of recent findings on miRNA/DDR in determining chemotherapy response in cancer patients, and the use of these biomarkers for novel potential therapeutic approaches. EXPERT OPINION: Defects in the DDR and deregulation of miRNAs are important hallmarks of human cancer. A full understanding of the mechanisms underlying the connection between miRNAs and DDR/DNA repair pathways will positively impact our knowledge on human tumor biology and on different responses to distinct drugs. Specific miRNAs interact with distinct DDR components and are promising targets for enhancing the effects of, and/or to overcome the resistance to, conventional chemotherapeutic agents. Finally, the development of innovative tools to deliver miRNA-targeting oligonucleotides may represents novel types of cancer interventions in clinic.
[Mh] MeSH terms primary: DNA Damage/physiology
DNA Repair/physiology
Drug Delivery Systems/trends
Gene Targeting/trends
MicroRNAs/physiology
Neoplasms/genetics
Neoplasms/therapy
[Mh] MeSH terms secundary: Animals
Antineoplastic Agents/administration & dosage
Apoptosis/drug effects
Apoptosis/physiology
DNA Damage/drug effects
DNA Repair/drug effects
Genomic Instability/physiology
Humans
MicroRNAs/antagonists & inhibitors
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; REVIEW
[Nm] Name of substance:0 (Antineoplastic Agents); 0 (MicroRNAs)
[Em] Entry month:1507
[Cu] Class update date: 150822
[Lr] Last revision date:150822
[Js] Journal subset:IM
[Da] Date of entry for processing:141011
[St] Status:MEDLINE
[do] DOI:10.1517/14712598.2014.950650


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