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hallmarks_of_cancer

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601

21975289_10

When the infiltration lymphocytes including CD4+ CD25+ T cells were added to the mixed lymphocyte reaction activated by autologous tumor lysate-pulsed dendritic cells , the proliferation of lymphocytes was inhibited .

602

21975289_11

CONCLUSION The increase of CD4+ CD25+ T cells in the tumor microenvironment correlates with tumor sizes .

603

21975289_12

These CD4+ CD25+ regulatory T cells appeared to suppress the immune response activated by dendritic cells .

604

20107609_0

Topoisomerase inhibitors such as camptothecin and etoposide are used as anti-cancer drugs and induce double-strand breaks ( DSBs ) in genomic DNA in cycling cells .

605

20107609_1

These DSBs are often covalently bound with polypeptides at the 3 ' and 5 ' ends .

606

20107609_2

Such modifications must be eliminated before DSB repair can take place , but it remains elusive which nucleases are involved in this process .

607

20107609_3

Previous studies show that CtIP plays a critical role in the generation of 3 ' single-strand overhang at " clean " DSBs , thus initiating homologous recombination ( HR)-dependent DSB repair .

608

20107609_4

To analyze the function of CtIP in detail , we conditionally disrupted the CtIP gene in the chicken DT40 cell line .

609

20107609_5

We found that CtIP is essential for cellular proliferation as well as for the formation of 3 ' single-strand overhang , similar to what is observed in DT40 cells deficient in the Mre11/Rad50/Nbs1 complex .

610

20107609_6

We also generated DT40 cell line harboring CtIP with an alanine substitution at residue Ser332 , which is required for interaction with BRCA1 .

611

20107609_7

Although the resulting CtIP(S332A/-/-) cells exhibited accumulation of RPA and Rad51 upon DNA damage , and were proficient in HR , they showed a marked hypersensitivity to camptothecin and etoposide in comparison with CtIP(+/-/-) cells .

612

20107609_8

Finally , CtIP(S332A/-/-)BRCA1(-/-) and CtIP(+/-/-)BRCA1(-/-) showed similar sensitivities to these reagents .

613

20107609_9

Taken together , our data indicate that , in addition to its function in HR , CtIP plays a role in cellular tolerance to topoisomerase inhibitors .

614

20107609_10

We propose that the BRCA1-CtIP complex plays a role in the nuclease-mediated elimination of oligonucleotides covalently bound to polypeptides from DSBs , thereby facilitating subsequent DSB repair .

615

22832494_0

Nonmelanoma skin cancer ( NMSC ) is by far the most frequent type of cancer in humans .

616

22832494_1

NMSC includes several types of malignancies with different clinical outcomes , the most frequent being basal and squamous cell carcinomas .

617

22832494_2

We have used the Sleeping Beauty transposon/transposase system to identify somatic mutations associated with NMSC .

618

22832494_3

Transgenic mice bearing multiple copies of a mutagenic Sleeping Beauty transposon T2Onc2 and expressing the SB11 transposase under the transcriptional control of regulatory elements from the keratin K5 promoter were treated with TPA , either in wild-type or Ha-ras mutated backgrounds .

619

22832494_4

After several weeks of treatment , mice with transposition developed more malignant tumors with decreased latency compared with control mice .

620

22832494_5

Transposon/transposase animals also developed basal cell carcinomas .

621

22832494_6

Genetic analysis of the transposon integration sites in the tumors identified several genes recurrently mutated in different tumor samples , which may represent novel candidate cancer genes .

622

22832494_7

We observed alterations in the expression levels of some of these genes in human tumors .

623

22832494_8

Our results show that inactivating mutations in Notch1 and Nsd1 , among others , may have an important role in skin carcinogenesis .

624

23264221_0

Pterostilbene , a polyphenolic compound present in grapes and other fruits , has been demonstrated to inhibit growth and induce apoptosis and autophagy in some cancer cell types .

625

23264221_1

We found that pterostilbene at the IC90 concentration of 44 �M inhibited proliferation and induced apoptosis in MOLT4 human leukemia cells .

626

23264221_2

Treatment with pterostilbene resulted in a transient accumulation of cells in the G0/G1-cell cycle phase followed by the S-phase arrest .

627

23264221_3

Pterostilbene-induced apoptotic death of MOLT4 cells was mediated by caspase-3 activation and was accompanied by the disruption of mitochondrial membrane potential , phosphatidylserine externalization and internucleosomal DNA fragmentation .

628

23264221_4

Our results suggest that pterostilbene could serve as a potential additional chemotherapeutic agent for the treatment of leukemia .

629

22201685_0

The innate immune response involves a variety of inflammatory reactions that can result in inflammatory disease and cancer if they are not resolved and instead are allowed to persist .

630

22201685_1

The effective activation and resolution of innate immune responses relies on the production and posttranscriptional regulation of mRNAs encoding inflammatory effector proteins .

631

22201685_2

The RNA-binding protein HuR binds to and regulates such mRNAs , but its exact role in inflammation remains unclear .

632

22201685_3

Here we show that HuR maintains inflammatory homeostasis by controlling macrophage plasticity and migration .

633

22201685_4

Mice lacking HuR in myeloid-lineage cells , which include many of the cells of the innate immune system , displayed enhanced sensitivity to endotoxemia , rapid progression of chemical-induced colitis , and severe susceptibility to colitis-associated cancer .

634

22201685_5

The myeloid cell-specific HuR-deficient mice had an exacerbated inflammatory cytokine profile and showed enhanced CCR2-mediated macrophage chemotaxis .

635

22201685_6

At the molecular level , activated macrophages from these mice showed enhancements in the use of inflammatory mRNAs ( including Tnf , Tgfb , Il10 , Ccr2 , and Ccl2 ) due to a lack of inhibitory effects on their inducible translation and/or stability .

636

22201685_7

Conversely , myeloid overexpression of HuR induced posttranscriptional silencing , reduced inflammatory profiles , and protected mice from colitis and cancer .

637

22201685_8

Our results highlight the role of HuR as a homeostatic coordinator of mRNAs that encode molecules that guide innate inflammatory effects and demonstrate the potential of harnessing the effects of HuR for clinical benefit against pathologic inflammation and cancer .

638

22945332_0

Therapy-induced cellular senescence ( TCS ) , characterized by prolonged cell cycle arrest , is an in vivo response of human cancers to chemotherapy and radiation .

639

22945332_1

Unfortunately , TCS is reversible for a subset of senescent cells , leading to cellular reproliferation and ultimately tumor progression .

640

22945332_2

This invariable consequence of TCS recapitulates the clinical treatment experience of patients with advanced cancer .

641

22945332_3

We report the findings of a clinicopathological study in patients with locally advanced non-small cell lung cancer demonstrating that marker of in vivo TCS following neoadjuvant therapy prognosticate adverse clinical outcome .

642

22945332_4

In our efforts to elucidate key molecular pathways underlying TCS and cell cycle escape , we have previously shown that the deregulation of mitotic kinase Cdk1 and its downstream effectors are important mediators of survival and cell cycle reentry .

643

22945332_5

We now report that aberrant expression of Cdk1 interferes with apoptosis and promotes the formation of polyploid senescent cells during TCS .

644

22945332_6

These polyploid senescent cells represent important transition states through which escape preferentially occurs .

645

22945332_7

The Cdk1 pathway is in part modulated differentially by p21 and p27 two members of the KIP cyclin-dependent kinase inhibitor family during TCS .

646

22945332_8

Altogether , these studies underscore the importance of TCS in cancer therapeutics .

647

22806877_0

PURPOSE We describe the anticancer activity of ganetespib , a novel non-geldanamycin heat shock protein 90 ( HSP90 ) inhibitor , in non-small cell lung cancer ( NSCLC ) models .

648

22806877_1

EXPERIMENTAL DESIGN The activity of ganetespib was compared with that of the geldanamycin 17-AAG in biochemical assays , cell lines , and xenografts , and evaluated in an ERBB2 YVMA-driven mouse lung adenocarcinoma model .

649

22806877_2

RESULTS Ganetespib blocked the ability of HSP90 to bind to biotinylated geldanamycin and disrupted the association of HSP90 with its cochaperone , p23 , more potently than 17-AAG .

650

22806877_3

In genomically defined NSCLC cell lines , ganetespib caused depletion of receptor tyrosine kinases , extinguishing of downstream signaling , inhibition of proliferation and induction of apoptosis with IC(50) values ranging 2 to 30 nmol/L , substantially lower than those required for 17-AAG ( 20-3,500 nmol/L ) .

651

22806877_4

Ganetespib was also approximately 20-fold more potent in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants .

652

22806877_5

In mice bearing NCI-H1975 ( EGFR L858R/T790M ) xenografts , ganetespib was rapidly eliminated from plasma and normal tissues but was maintained in tumor with t(1/2) 58.3 hours , supporting once-weekly dosing experiments , in which ganetespib produced greater tumor growth inhibition than 17-AAG .

653

22806877_6

However , after a single dose , reexpression of mutant EGFR occurred by 72 hours , correlating with reversal of antiproliferative and proapoptotic effects .

654

22806877_7

Consecutive day dosing resulted in xenograft regressions , accompanied by more sustained pharmacodynamic effects .

655

22806877_8

Ganetespib also showed activity against mouse lung adenocarcinomas driven by oncogenic ERBB2 YVMA .

656

22806877_9

CONCLUSIONS Ganetespib has greater potency than 17-AAG and potential efficacy against several NSCLC subsets , including those harboring EGFR or ERBB2 mutation .

657

23167379_0

Breast cancer causes death due to distant metastases in which tumor cells produce matrix metalloproteinase ( MMP ) enzymes which facilitate invasion .

658

23167379_1

Oleuropein , the main olive oil polyphenol , has anti-proliferative effects .

659

23167379_2

This study aimed to investigate the effect of oleuropein on the metastatic and anti-metastatic gene expression in the MDA human breast cancer cell line .

660

23167379_3

We evaluated the MMPs and TIMPs gene expression by semi-quantitative reverse transcriptase polymerase chain reaction ( RT-PCR ) in treated and untreated cells .

661

23167379_4

This study demonstrated that OL may induce anti-metastatic effects on human breast cancer cells .

662

23167379_5

We found that TIMP1,-3 , and -4 were over-expressed after all periods of incubation in treated cancer cells compared to untreated cells , while MMP2 and MMP9 genes were down-regulated , at least initially .

663

23167379_6

Treatment of breast cancer cells with oleuropein could help in prevention of cancer metastasis by increasing the TIMPs and suppressing the MMPs gene expressions .

664

21195136_0

Modeling the behavior of mammalian arachnoid cells is critical to understand hydrocephalus and other brain disorders involving abnormal flow of cerebrospinal fluid , yet relatively little is known about the physiology of arachnoid cells due to lack of a robust three-dimensional model system .

665

21195136_1

Explanted primary cultures have been the only option to study transport across arachnoid cell membranes , but practical limitations of primary culture include slow growth , early senescence , and poor reproducibility .

666

21195136_2

The purpose of this study was to create immortalized rat arachnoid cell lines to permit in vitro study of arachnoid granulations and properties of cerebrospinal fluid ( CSF ) flow .

667

21195136_3

We established and partially characterized two immortalized cell lines generated from primary rat arachnoid cells , using retroviral gene transfer of SV40 large T antigen ( SV40 LTAg ) either with or without human telomerase ( hTERT ) .

668

21195136_4

The established cell lines stably express either SV40 LTAg alone , or SV40 LTAg and hTERT , and demonstrate high proliferative rate , contact inhibition at confluence , and stable expression of protein markers characteristic of native arachnoid cells over more than 160 passages .

669

23131583_0

Chromosomal translocations typically impair cell differentiation and often require secondary mutations for malignant transformation .

670

23131583_1

However , the role of a primary translocation in the development of collaborating mutations is debatable .

671

23131583_2

To delineate the role of leukemic translocation NUP98-HOXD13 ( NHD13 ) in secondary mutagenesis , DNA break and repair mechanisms in stimulated mouse B lymphocytes expressing NHD13 were analyzed .

672

23131583_3

Our results showed significantly reduced expression of non-homologous end joining ( NHEJ)-mediated DNA repair genes , DNA Pkcs , DNA ligase4 , and Xrcc4 leading to cell cycle arrest at G2/M phase .

673

23131583_4

Our results showed that expression of NHD13 fusion gene resulted in impaired NHEJ-mediated DNA break repair .

674

23230145_0

The tumor suppressors Lats1 and Lats2 are mediators of the Hippo pathway that regulates tissue growth and proliferation .

675

23230145_1

Their N-terminal non-kinase regions are distinct except for Lats conserved domains 1 and 2 ( LCD1 and LCD2 ) , which may be important for Lats1/2-specific functions .

676

23230145_2

Lats1 knockout mice were generated by disrupting the N-terminal region containing LCD1 ( Lats1(\u0394N/\u0394N) ) .

677

23230145_3

Some Lats1(\u0394N/\u0394N) mice were born safely and grew normally .

678

23230145_4

However , mouse embryonic fibroblasts ( MEFs ) from Lats1(\u0394N/\u0394N) mice displayed mitotic defects , centrosomal overduplication , chromosomal misalignment , multipolar spindle formation , chromosomal bridging and cytokinesis failure .

679

23230145_5

They also showed anchorage-independent growth and continued cell cycles and cell growth , bypassing cell-cell contact inhibition similar to tumor cells .

680

23230145_6

Lats1(\u0394N/\u0394N) MEFs produced tumors in nude mice after subcutaneous injection , although the tumor growth rate was much slower than that of ordinary cancer cells .

681

23230145_7

Yap , a key transcriptional coactivator of the Hippo pathway , was overexpressed and stably retained in Lats1(\u0394N/\u0394N) MEFs in a cell density independent manner , and Lats2 mRNA expression was downregulated .

682

23230145_8

In conclusion , N-terminally truncated Lats1 induced Lats2 downregulation and Yap protein accumulation , leading to chromosomal instability and tumorigenesis .

683

12220644_0

The G protein-coupled human gastrin-releasing peptide receptor ( hGRP-R ) is frequently found aberrantly expressed in human cancers of the colon , stomach , and lung , and its ligand-specific activation has been implicated in cell proliferation and differentiation .

684

12220644_1

Here , we demonstrated hGRP-R activation stimulated sustained cyclic AMP response element binding protein ( CREB ) phosphorylation and transactivation in duodenal cancer cells through a protein kinase C and partially p38 mitogen-activated protein kinase-dependent pathway .

685

12220644_2

In contrast , intracellular calcium , ERK1/2 , protein kinase A , and PI3 kinase were not involved .

686

12220644_3

This novel signaling mechanism might be of importance for regulation of CREB-dependent gene expression in human cancer expressing functional hGRP-R .

687

22794249_0

Cardiac \u03b1-tropomyosin ( Tm ) single-site mutations D175N and E180G cause familial hypertrophic cardiomyopathy ( FHC ) .

688

22794249_1

Previous studies have shown that these mutations increase both Ca(2+) sensitivity and residual contractile activity at low Ca(2+) concentrations , which causes incomplete relaxation during diastole resulting in hypertrophy and sarcomeric disarray .

689

22794249_2

However , the molecular basis for the cause and the difference in the severity of the manifested phenotypes of disease are not known .

690

22794249_3

In this work we have ( 1 ) used ATPase studies using reconstituted thin filaments in solution to show that these FHC mutants result in an increase in Ca(2+) sensitivity and an increased residual level of ATPase , ( 2 ) shown that both FHC mutants increase the rate of cleavage at R133 , residues N-terminal to the mutations , when free and bound to actin , ( 3 ) shown that for Tm-E180G , the increase in the rate of cleavage is greater than that for D175N , and ( 4 ) shown that for E180G , cleavage also occurs at a new site 53 residues C-terminal to E180G , in parallel with cleavage at R133 .

691

22794249_4

The long-range decreases in dynamic stability due to these two single-site mutations suggest increases in flexibility that may weaken the ability of Tm to inhibit activity at low Ca(2+) concentrations for D175N and to a greater degree for E180G , which may contribute to differences in the severity of FHC .

692

20693267_0

The authors examined nutritional risk factors for prostate cancer among 9,559 participants in the Prostate Cancer Prevention Trial ( United States and Canada , 1994-2003 ) .

693

20693267_1

The presence or absence of cancer was determined by prostate biopsy , which was recommended during the trial because of an elevated prostate-specific antigen level or an abnormal digital rectal examination and was offered to all men at the trial's end .

694

20693267_2

Nutrient intake was assessed using a food frequency questionnaire and a structured supplement-use questionnaire .

695

20693267_3

Cancer was detected in 1,703 men ; 127 cancers were high-grade ( Gleason score 8-10 ) .

696

20693267_4

There were no associations of any nutrient or supplement with prostate cancer risk overall .

697

20693267_5

Risk of high-grade cancer was associated with high intake of polyunsaturated fats ( quartile 4 vs. quartile 1 : odds ratio = 2.41 , 95% confidence interval ( CI ) : 1.33 , 4.38 ) .

698

20693267_6

Dietary calcium was positively associated with low-grade cancer but inversely associated with high-grade cancer ( for quartile 4 vs. quartile 1 , odds ratios were 1.27 ( 95% CI : 1.02 , 1.57 ) and 0.43 ( 95% CI : 0.21 , 0.89 ) , respectively ) .

699

20693267_7

Neither dietary nor supplemental intakes of nutrients often suggested for prostate cancer prevention , including lycopene , long-chain n-3 fatty acids , vitamin D , vitamin E , and selenium , were significantly associated with cancer risk .

700

20693267_8

High intake of n-6 fatty acids , through their effects on inflammation and oxidative stress , may increase prostate cancer risk .