Background
The study aims are to evaluate the associations between nasopharyngeal carcinoma (NPC) risk and cigarette smoking and to explore the effects of cigarette smoking on Epstein‐Barr virus ...(EBV) infection for NPC risk.
Methods
1235 male NPC cases and 1262 hospital‐based male controls matched to cases were recruited across six collaborative hospitals between 2010 and 2014. Using a standardized questionnaire, information on cigarette smoking and other potential risk factors for NPC was obtained. Blood was collected and used for anti‐EBV VCA IgA and anti‐EBV EA‐EBNA1 IgA testing using standard methods. Unconditional logistic regression analysis was used to estimate odds ratio (OR) with 95% confidence interval (CI) for each risk factor after adjusting for confounders.
Results
63.6% of cases and 44.0% of controls reported ever smoking cigarettes. After full adjustment, current smokers had a significant 1.60‐fold (95% CI = 1.30‐1.97) and former smokers a borderline significant 1.27‐fold (95% CI = 1.00‐1.60) increased NPC risk compared to never smokers. NPC risk increased with increasing duration, intensity, and pack‐years of cigarette smoking but not with age at smoking initiation. Among controls, anti‐EBV VCA IgA seropositivity rate was higher in current smokers than never smokers (14.0% vs 8.4%; OR = 1.82; 95% CI = 1.19‐2.79). Mediation analyses showed that more than 90% of the cigarette smoking effect on NPC risk is mediated through anti‐EBV VCA IgA.
Conclusion
This study confirms the association between long‐term cigarette smoking and NPC and demonstrates that current smoking is associated with seropositivity of anti‐EBV VCA IgA antibodies.
Smoking duration and intensity but not age at initiation are NPC risk factors, and anti‐EBV VCA IgA seropositivity rate was higher in current than never smokers among controls. Mediation analyses show that NPC and EBV association may be explained by the interplay between smoking and EBV antibodies serostatus.
Genetic susceptibility is associated with nasopharyngeal carcinoma (NPC). We previously identified rare variants potentially involved in familial NPC and common variants significantly associated with ...sporadic NPC.
We conducted targeted gene sequencing of 20 genes 16 identified from the study of multiplex families, three identified from a pooled analysis of NPC genome-wide association study (GWAS), and one identified from both studies among 819 NPC cases and 938 controls from two case-control studies in Taiwan (independent from previous studies). A targeted, multiplex PCR primer panel was designed using the custom Ion AmpliSeq Designer v4.2 targeting the regions of the selected genes. Gene-based and single-variant tests were conducted.
We found that NPC was associated with combined common and rare variants in
(
= 1.3 × 10
),
(
= 1.6 × 10
),
(
= 4.0 × 10
), and
(
= 5.4 × 10
). Such associations were likely driven by common variants within these genes, based on gene-based analyses evaluating common variants and rare variants separately (e.g., for common variants of
= 4.6 × 10
; for rare variants,
= 0.04). We also observed a suggestive association with rare variants in
(
= 3.8 × 10
) for NPC risk. In addition, we validated four previously reported NPC risk-associated SNPs.
Our findings confirm previously reported associated variants and suggest that some common variants in genes previously linked to familial NPC are associated with the development of sporadic NPC.
NPC-associated genes, including
, and
, suggest a role for telomere length maintenance in NPC etiology.
A study of nanoporous polymer gratings, with controllable nanostructured porosity, as a function of grating performance, photopolymerization kinetics and morphology is presented. Modifying the ...standard holographic polymer dispersed liquid crystal (H-PDLC) system, by including a non-reactive solvent, results in a layered, nanoporous morphology and produces reflective optical elements with excellent optical performance of broadband reflection. The addition of the non-reactive solvent in the pre-polymer mixture results in a morphology typified by void/polymer layer-by-layer structures if sufficient optical energy is used during the holographic writing process. The duration and intensity of optical exposure necessary to form well-aligned nanoporous structures can only be obtained in the modified system by (a) illumination under longer time of holographic interference patterning (30
min) or (b) illumination under very short time of holographic interference patterning (30
s) and followed by post-curing using homogeneous optical exposure for 60
min. Comparatively, a typical H-PDLC is formed in less than 1
min. To further understand the differences in the formation of these two analogous materials, the temporal dynamics of the photoinitiation and polymerization (propagation) kinetics were examined. It is shown herein that the writing exposure gives a cross-linked polymer network that is denser in the bright regions. With 60% (or even 45%) acrylate conversion, almost no free monomer would be left after the writing. Continued exposure serves primarily to add cross-links. This has the tendency to collapse the network, especially the less dense portions, which in effect get glued down to the more dense parts. To the extent that the solvent increases the mobility of the polymer network, this process will be aided. Equally important, the size of the periodic nanopores can be varied from 10 to 50
nm by controlling either the LC concentration in the pre-polymer mixture or by controlling the time of the homogeneous post-cure.
Introduction: Interleukin 2 receptor-α (CD25) expression on myeloid leukemic blasts may be a marker for chemotherapy-resistant leukemia stem cells (Saito et al., 2010) and has been associated with ...poor overall survival (OS) in AML patients (pts) <60 years treated with cytotoxic chemotherapy (Terwijn et al., 2009; Gonen et al., 2012; Cerny et al., 2013). The prognostic impact of CD25 expression in older pts remains unclear. We therefore retrospectively analyzed CD25 expression in baseline bone marrow (BM) of newly diagnosed AML pts >60 years enrolled in a Phase I clinical trial combining the CXCR4 antagonist, plerixafor and the DNA methyltransferase inhibitor, decitabine (Roboz et al., 2013).
Methods: BM aspirates were available for 69 newly diagnosed older AML pts treated with 1-4 cycles of 5 days of plerixafor combined with 10 days of decitabine. Pts with favorable risk cytogenetic or mutational profiles were excluded from the clinical trial. Multi-parameter flow cytometry was used to evaluate the expression of CD25 in blast and progenitor (CD34+) populations. Cells were gated on CD45dim/SSClo characteristics. Pts were considered positive (CD25+) when greater than 10% of the gated population expressed CD25.
Results: Of 69 pts, 58 were evaluable for survival and 57 for response; one pt died prior to scheduled response assessment. Of 58 pts evaluated at baseline (pre-treatment BM), 20 (34.5%) were CD25+ vs. 38 (65.5%) CD25-negative (CD25-). CD25+ pts had significantly inferior median OS (152 days vs. 419 days, p=0.003) and were at higher risk of dying within 1 year of diagnosis, relative risk (RR) 1.58 (95% 1.04-2.41). Similarly, pts surviving less than 1 year had significantly higher percentages of CD34+ cells expressing CD25 than those who lived greater than 1 year (7.82% vs. 4.77%, p=0.028). CD25+ pts were less likely to respond to therapy, RR 1.90 (95% CI 1.23-2.93) and, in turn, pts who were resistant to therapy had higher baseline CD25 expression level than those who responded (7.82% vs. 4.87%, p=0.033).
Five CD25+ pts (25%) and 12 CD25- pts (32%) received an allogeneic transplant. Transplanted CD25+ pts had improved OS vs. CD25+ pts without transplant, (median OS not reached (NR) vs. 107 days), p=0.005. In contrast, there was no significant difference in survival between CD25- pts with and without allogeneic transplant, p=0.96. Also, there was no difference in median OS between CD25+ pts receiving transplant vs. CD25- pts (median OS NR vs. 419 days), p<0.40. There was no difference in survival between CD25+ pts with intermediate risk cytogenetics vs. CD25+ pts with unfavorable cytogenetics (OS 153 vs. 172, p=0.77). Lastly, CD25+ pts had significantly worse OS compared to CD25- pts with unfavorable cytogenetics, (median OS 152 vs. 333 days) respectively, p=0.05.
Compared to CD25- pts, CD25+ pts were older (median age 74.5 vs. 71.5, p=0.096), more likely to be male (75% vs. 47.3%, p=0.055) and had higher baseline WBC (19x1000/uL vs. 5x1000/uL, p=0.089) and pretreatment lactate dehydrogenase (LDH) (median 365 vs. 271, p=0.04). Analysis of diagnosis BM blast percentage yielded no difference between CD25+ and CD25- pts (62% and 46%, p=0.44). Sixteen (80%) and 4 (20%) of CD25+ patients had intermediate and unfavorable cytogenetics vs. 21 (55%) and 17 (44%) CD25- pts respectively, p=0.09. No significant difference between groups was noted when evaluating the mutational status of TET2, TP53, RUNX1, DNMT3A, NPM1, or FLT3.
Conclusions: Interleukin 2 Receptor-α expression on leukemic blasts is known to correlate with poor prognosis and OS in young pts with AML who have been treated with cytotoxic chemotherapy. We have demonstrated that >10% CD25 expression on CD34+ blasts is associated with poor OS and resistance to therapy in AML pts > 60years of age treated with the combination of plerixafor and decitabine. Pts with >10% CD25 expression on CD34+ cells were at increased risk of death within one year and increased risk of resistance to induction therapy. Thirty-four percent of the pts in this study were CD25+, consistent with previous reports (Terwijn et al., 2009). This study highlights the importance of CD25 expression on CD34+ leukemic cells in determining prognosis, OS, response to hypomethylating agent therapy and benefit of transplant in older pts with newly diagnosed AML. Further investigations into the aggressive nature of CD25+ AML, mechanisms of resistance and novel therapeutics are ongoing.
Roboz:Teva Oncology: Consultancy; Novartis: Consultancy; Sunesis: Consultancy; Astra Zeneca: Consultancy; Glaxo SmithKline: Consultancy; Celgene: Consultancy; Agios: Consultancy; Novartis: Consultancy; Astex: Consultancy. Ritchie:Celgene, Incyte: Speakers Bureau.
To celebrate the success of the Journal of Controlled Release and the research covered in the journal, here we highlight some of the most cited research articles in the history of the journal. Based ...on the literature search in Google Scholar in July 2013, we identified ~30 research articles that have received most number of citations. Authors of these articles were invited to provide a commentary on these articles. This compilation of commentaries gives a historical perspective and current status of research covered in these articles.
The Gamma database machine project DeWitt, D.J.; Ghandeharizadeh, S.; Schneider, D.A. ...
IEEE transactions on knowledge and data engineering,
03/1990, Letnik:
2, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The design of the Gamma database machine and the techniques employed in its implementation are described. Gamma is a relational database machine currently operating on an Intel iPSC/2 hypercube with ...32 processors and 32 disk drives. Gamma employs three key technical ideas which enable the architecture to be scaled to hundreds of processors. First, all relations are horizontally partitioned across multiple disk drives, enabling relations to be scanned in parallel. Second, parallel algorithms based on hashing are used to implement the complex relational operators, such as join and aggregate functions. Third, dataflow scheduling techniques are used to coordinate multioperator queries. By using these techniques, it is possible to control the execution of very complex queries with minimal coordination. The design of the Gamma software is described and a thorough performance evaluation of the iPSC/s hypercube version of Gamma is presented.< >
The silatecan 7-tert-butyldimethylsilyl-10-hydroxy-camptothecin (DB-67) represents a new generation of camptothecin derivatives that exhibits a potent in vitro DNA topoisomerase I (TOP1)-mediated ...DNA-damaging activity, improved blood stability, and holds significant promise for the treatment of human cancers. In this study, we characterize the role of TOP1 in mediating the radiosensitization activity of DB-67. As examined by clonogenic survival assay, DB-67 exhibited potent radiosensitization activity at a concentration 10-fold lower than camptothecin in the human glioma D54-MG and T-98G cells, which harbor wild-type and mutant p53, respectively. Analyzed by the single-hit multitarget model, DB-67 induced radiosensitization by obliterating the "shoulder" of the radiation survival curve in the D54-MG cells. The in vivo targeting of TOP1 by DB-67 was investigated by immunoblot analysis. In a dose-dependent manner, DB-67 specifically stimulates covalent linking of TOP1 to chromosomal DNA at concentrations 10-fold lower than camptothecin in the D54-MG cells. The potency of in vivo targeting of TOP1 by DB-67 correlates well with its cytotoxicity and radiosensitization activity. Furthermore, DB-67 exhibited substantially less cytotoxicity and radiosensitization activity in the TOP1 mutant Chinese hamster lung fibroblast DC3F/C-10 cells than in their parental DC3F cells. Together, our data show that DB-67 exhibits potent cytotoxicity and radiosensitization activity by targeting TOP1 in mammalian cells and has great potential for being developed to treat human cancers.
PDF
