pinecone/core-2020-05-10-deduplication huggingface dataset:
IGF binding protein‐6 expression in vascular endothelial cells is induced by hypoxia and plays a negative role in tumor angiogenesis

Hypoxia stimulates tumor angiogenesis by inducing the expression of angiogenic molecules. The negative regulators of this process, however, are not well understood. Here, we report that hypoxia induced the expression of insulin‐like growth factor binding protein‐6 (IGFBP‐6), a tumor repressor, in human and rodent vascular endothelial cells (VECs)  via  a hypoxia‐inducible factor (HIF)‐mediated mechanism. Addition of human IGFBP‐6 to cultured human VECs inhibited angiogenesis  in vitro . An IGFBP‐6 mutant with at least 10,000‐fold lower binding affinity for IGFs was an equally potent inhibitor of angiogenesis, suggesting that this action of IGFBP‐6 is IGF‐independent. The functional relationship between IGFBP‐6 and vascular endothelial growth factor (VEGF), a major hypoxia‐inducible angiogenic molecule, was examined. While VEGF alone increased angiogenesis  in vitro , co‐incubation with IGFBP‐6 abolished VEGF‐stimulated angiogenesis. The  in vivo  role of IGFBP‐6 in angiogenesis was tested in  flk1 :GFP zebrafish embryos, which exhibit green fluorescence protein in developing vascular endothelium, permitting visualization of developing blood vessels. Injection of human IGFBP‐6 mRNA reduced the number of embryonic inter‐segmental blood vessels by ∼40%. This anti‐angiogenic activity is conserved in zebrafish because expression of zebrafish IGFBP‐6b had similar effects. To determine the anti‐angiogenic effect of IGFBP‐6 in a tumor model, human Rh30 rhabdomyosarcoma cells stably transfected with IGFBP‐6 were inoculated into athymic BALB/c nude mice. Vessel density was 52% lower in IGFBP‐6‐transfected xenografts than in vector control xenografts. These results suggest that the expression of IGFBP‐6 in VECs is up‐regulated by hypoxia and IGFBP‐6 inhibits angiogenesis  in vitro  and  in vivo
The age‐specific prevalence of human papillomavirus and risk of cytologic abnormalities in rural Nigeria: Implications for screen‐and‐treat strategies

Cervical screening for carcinogenic human papillomavirus (HPV) infection is being considered for low‐income countries. Effectiveness requires targeted screening in older women in whom prevalent infections are more likely to be persistent and predictive of precancer. Some studies in West Africa have found unusually high HPV prevalences across all adult ages, which may reduce the positive predictive value (PPV) of HPV‐based screening, if positivity in older women does not sufficiently predict elevated risk. We conducted a population‐based study in rural Nigeria to identify HPV prevalence and associated cervical abnormalities. Using stratified random sampling, we enrolled women age 15+. Nonvirgins had a cervical exam including liquid‐based cytology and PCR HPV DNA testing from residual cytology specimens. Two‐thirds of invited women participated, and 14.7% had detectable carcinogenic HPV, a proportion that did not decline with age ( p ‐trend = 0.36) and showed slight peaks in the 15–29 and 60–69 age groups. Among women of the age typically considered for screen‐and‐treat programs (30–49 years), 12.8% were HPV positive, and the PPV for high‐grade or worse cytology was 16.4%. Comparatively, women age < 30 were more likely to be HPV positive (18.9%,  p  = 0.03) with a lower PPV (4.2%  p  = 0.05). Among women age 50+ (typically excluded from screening in resource‐poor settings because inexpensive treatment is not available), HPV positivity was 14.2% with a PPV of 13.9%. In Irun and similar settings where HPV does not decline with age, HPV‐based screen‐and‐treat programs might be feasible for mid‐adult women because prevalence is sufficiently low and positivity predicts elevated risk of more easily treated precancer
Role of exosomes released by chronic myelogenous leukemia cells in angiogenesis

The present study is designed to assess if exosomes released from Chronic Myelogenous Leukemia (CML) cells may modulate angiogenesis. We have isolated and characterized the exosomes generated from LAMA84 CML cells and demonstrated that addition of exosomes to\ud
human vascular endothelial cells (HUVEC) induces an increase of both ICAM-1 and VCAM-1 cell adhesion molecules and interleukin-8 expression. The stimulation of cell-cell adhesion\ud
molecules was paralleled by a dose-dependent increase of adhesion of CML cells to a HUVEC\ud
monolayer. We further showed that the treatment with exosomes from CML cells caused an increase in endothelial cell motility accompanied by a loss of VE-cadherin and β-catenin from the\ud
endothelial cell surface. Functional characterization of exosomes isolated from CML patients\ud
confirmed the data obtained with exosomes derived from CML cell line. CML exosomes caused reorganization into tubes of HUVEC cells cultured on Matrigel. When added to Matrigel plugs in vivo, exosomes induced ingrowth of murine endothelial cells and vascularization of the Matrigel\ud
plugs. Our results suggest for the first time that exosomes released from CML cells directly affect endothelial cells modulating the process of neovascularization
An American founder mutation in  MLH1

Mutations in the mismatch repair genes cause Lynch syndrome (LS), conferring high risk of colorectal, endometrial and some other cancers. After the same splice site mutation in the  MLH1  gene (c.589‐2A>G) had been observed in four ostensibly unrelated American families with typical LS cancers, its occurrence in comprehensive series of LS cases (Mayo Clinic, Germany and Italy) was determined. It occurred in 10 out of 995 LS mutation carriers (1.0%) diagnosed in the Mayo Clinic diagnostic laboratory. It did not occur among 1,803 cases tested for  MLH1  mutations by the German HNPCC consortium, while it occurred in three probands and an additional five family members diagnosed in Italy. In the U.S., the splice site mutation occurs on a large (∼4.8 Mb) shared haplotype that also harbors the variant c.2146G>A, which predicts a missense change in codon 716 referred to here as V716M. In Italy, it occurs on a different, shorter shared haplotype (∼2.2 Mb) that does not carry V716M. The V716M variant was found to be present by itself in the U.S., German and Italian populations with individuals sharing a common haplotype of 280 kb, allowing us to calculate that the variant arose around 5,600 years ago (225 generations; 95% confidence interval 183–272). The splice site mutation in America arose or was introduced some 450 years ago (18 generations; 95% confidence interval 14–23); it accounts for 1.0% all LS in the Unites States and can be readily screened for
Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells.

T-cells specific for foreign (e.g., viral) antigens can give rise to strong protective immune responses, whereas self/tumor antigen-specific T-cells are thought to be less powerful. However, synthetic T-cell vaccines composed of Melan-A/MART-1 peptide, CpG and IFA can induce high frequencies of tumor-specific CD8 T-cells in PBMC of melanoma patients. Here we analyzed the functionality of these T-cells directly ex vivo, by multiparameter flow cytometry. The production of multiple cytokines (IFNγ, TNFα, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways. Interestingly, high frequencies of functionally competent T-cells were induced irrespective of patient's age or gender. Finally, CD8 T-cell function correlated with disease-free survival. However, this result is preliminary since the study was a Phase I clinical trial. We conclude that human tumor-specific CD8 T-cells can reach functional competence in vivo, encouraging further development and Phase III trials assessing the clinical efficacy of robust vaccination strategies
Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells?

Cancer stem cells (CSCs) are similar to normal stem cells in their ability to self-renew and to generate large populations of more differentiated descendants. In contrast to the hierarchical organization that is presumed to be the prevalent mode of normal tissue homeostasis, phenotypic plasticity allows cancer cells to dynamically enter into and exit from stem-cell states. The epithelial-mesenchymal transition (EMT) has been closely associated with the acquisition of both invasive and stem-cell properties in cancer cells. Thereby, EMT programs emerge as important regulators of phenotypic plasticity in cancer cells including their entrance into stem-cell states. Much is still to be learned about the regulation of EMTs through epigenetic mechanisms in cancer cells and the contributions that EMT programs make to normal tissue homeostasis.National Institutes of Health (U.S.) (Grant CA12515)National Cancer Institute (U.S.) (Grant CA12515)National Institutes of Health (U.S.) (Grant DE020817)National Cancer Institute (U.S.) (Grant DE020817
Characterization of a new trabectedin-resistant myxoid liposarcoma cell line that shows collateral sensitivity to methylating agents

Myxoid Liposarcomas (MLS), characterized by the expression of FUS-CHOP fusion gene are clinically very sensitive to the DNA binding antitumor agent, trabectedin. However, resistance eventually occurs, preventing disease eradication. To investigate the mechanisms of resistance, a trabectedin resistant cell line, 402-91/ET, was developed. The resistance to trabectedin was not related to the expression of MDR related proteins, uptake/efflux of trabectedin or GSH levels that were similar in parental and resistant cells. The 402-91/ET cells were hypersensitive to UV light because of a nucleotide excision repair defect: XPG complementation decreased sensitivity to UV rays, but only partially to trabectedin. 402-91/ET cells showed collateral sensitivity to temozolomide due to the lack of O(6) -methylguanine-DNA-methyltransferase (MGMT) activity, related to the hypermethylation of MGMT promoter. In 402-91 cells chromatin immunoprecipitation (ChIP) assays showed that FUS-CHOP was bound to the PTX3 and FN1 gene promoters, as previously described, and trabectedin caused FUS-CHOP detachment from DNA. Here we report that, in contrast, in 402-91/ET cells, FUS-CHOP was not bound to these promoters. Differences in the modulation of transcription of genes involved in different pathways including signal transduction, apoptosis and stress response between the two cell lines were found. Trabectedin activates the transcription of genes involved in the adipogenic-program such as c/EBPα and β, in 402-91 but not in 402-91/ET cell lines. The collateral sensitivity of 402-91/ET to temozolomide provides the rationale to investigate the potential use of methylating agents in MLS patients resistant to trabectedin
Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples.

Transcriptomic analysis of global gene expression in ovarian carcinoma can identify dysregulated genes capable to serve as molecular markers for histology subtypes and survival. The aim of our study was to validate previous candidate signatures in an independent setting and to identify single genes capable to serve as biomarkers for ovarian cancer progression. As several datasets are available in the GEO today, we were able to perform a true meta-analysis. First, 829 samples (11 datasets) were downloaded, and the predictive power of 16 previously published gene sets was assessed. Of these, eight were capable to discriminate histology subtypes, and none was capable to predict survival. To overcome the differences in previous studies, we used the 829 samples to identify new predictors. Then, we collected 64 ovarian cancer samples (median relapse-free survival 24.5 months) and performed TaqMan Real Time Polimerase Chain Reaction (RT-PCR) analysis for the best 40 genes associated with histology subtypes and survival. Over 90% of subtype-associated genes were confirmed. Overall survival was effectively predicted by hormone receptors (PGR and ESR2) and by TSPAN8. Relapse-free survival was predicted by MAPT and SNCG. In summary, we successfully validated several gene sets in a meta-analysis in large datasets of ovarian samples. Additionally, several individual genes identified were validated in a clinical cohort
The utility of serum CA-125 in predicting extra-uterine disease in apparent early stage endometrial cancer

Objectives:  \ud
To evaluate the clinical value of pre-operative serum CA125 in predicting the presence of extra-uterine disease in patients with apparent early stage endometrial cancer.  \ud
\ud
Methods:  \ud
Between October 6, 2005 and June 17, 2010, 760 patients were enrolled in an international, multicentre, prospective randomized trial (LACE) comparing laparotomy with laparoscopy in the management of endometrial cancer apparently confined to the uterus.  This study is based on data from 657 patients with endometrial adenocarcinoma who had a pre-operative serum CA125 value, and was undertaken to correlate pre-operative serum CA125 with final stage. \ud
\ud
Results:\ud
Using a pre-operative CA-125 cutpoint of 30U/ml was associated with the smallest misclassification error (14.5%) using a multiple cross-validation method. Median pre-operative serum CA-125 was 14U/ml, and using a cutpoint of 30U/ml, 14.9% of patients had elevated CA-125 levels. Of 98 patients with elevated CA-125 level, 36 (36.7%) had evidence of extra-uterine disease. Of the 116 patients (17.7%) with evidence of extra-uterine disease, 31.0% had elevated CA-125 level. In univariate and multivariate logistic regression analysis, only pre-operative CA-125 level was found to be associated with extra-uterine spread of disease. Utilising a cutpoint of 30U/ml achieved a sensitivity, specificity, positive predictive value and negative predictive value of 31.0%, 88.5%, 36.7% and 85.7% respectively. Overall, 326/657 (49.6%) of patients had full surgical staging involving lymph node dissection. When analysis was limited to patients that had undergone full surgical staging, the outcomes remained essentially unchanged.\ud
\ud
Conclusions:\ud
Elevated CA-125 above 30U/ml in patients with apparent early stage disease is associated with a sensitivity of 31.0% and specificity of 88.5% in detecting extra-uterine disease.  Pre-operative identification of this risk factor may assist to triage patients to tertiary centres and comprehensive surgical staging
Clinical implications of HPV in oropharyngeal cancer

Tonsillar cancer incidence has been increasing in Sweden and many other western
countries in the last decades despite that other head and neck cancers are decreasing. It
is now established that Human Papillomavirus (HPV) can be accredited part of that
increase.




The aims of this thesis were to investigate any change in incidence of base of tongue
cancer, any further increase of tonsillar cancer incidence, what role HPV may have, the
prognostic value of HPV as well as the outcome of different treatment regimes on
tonsillar cancer.



Using the Swedish Cancer Registry, we found that the incidence for both tonsillar and
base of tongue cancer has increased from 1970 to 2006-2007, for tonsillar cancer from
0.74/100000 person-years 1970-1979 to 1.65/100000 person-years 2000-2006 in
Stockholm County and for base of tongue cancer from 0.15/100000 person-years 1970-
1974 to 0.47/100000 person-years 2005-2007 in Sweden. We analyzed pre-treatment,
paraffin-embedded diagnostic tumor biopsies for HPV using PCR technique and found
that the proportion of HPV in both tonsillar and base of tongue cancer has increased
during the last decade, reaching 93% positivity in tonsillar cancer and 83% positivity in
base of tongue cancer in 2006-2007. To evaluate if HPV was transcriptionally active in
these biopsies, we also tested for HPV E6 and E7 mRNA, which was positive in the
vast majority of cases. For base of tongue cancer, HPV was found to be a significant
prognostic factor, with improved overall as well as disease free survival compared to
patients with HPV-negative tumors, irrespective of patient age, sex and tumor stage. It
has been suggested that patients with HPV positive tumors possibly could be cured by
less intense treatment and thus reducing side effects. When analyzing all HPV positive
tonsillar cancer patients in Stockholm County, Sweden between 2000 and 2007, we
compared survival and development of distant metastasis between groups that had
received three different treatment regimes. No significant difference in overall or
disease free survival was found between the treatment groups, but a trend of improved
survival for intensified treatment was seen that needs to be studied further.



The vast majority of HPV positive tonsillar- and base of tongue cancers are HPV16,
which means that the commercially available vaccines would protect against it. This
highlights the discussion if boys/men should be included in the HPV vaccination
program
Pregnancy-induced chromatin remodeling in the breast of postmenopausal women.

Early pregnancy and multiparity are known to reduce the risk of women to develop breast cancer at menopause. Based on the knowledge that the differentiation of the breast induced by the hormones of pregnancy plays a major role in this protection, this work was performed with the purpose of identifying what differentiation-associated molecular changes persist in the breast until menopause. Core needle biopsies (CNB) obtained from the breast of 42 nulliparous (NP) and 71 parous (P) postmenopausal women were analyzed in morphology, immunocytochemistry and gene expression. Whereas in the NP breast, nuclei of epithelial cells were large and euchromatic, in the P breast they were small and hyperchromatic, showing strong methylation of histone 3 at lysine 9 and 27. Transcriptomic analysis performed using Affymetrix HG_U133 oligonucleotide arrays revealed that in CNB of the P breast, there were 267 upregulated probesets that comprised genes controlling chromatin organization, transcription regulation, splicing machinery, mRNA processing and noncoding elements including XIST. We concluded that the differentiation process induced by pregnancy is centered in chromatin remodeling and in the mRNA processing reactome, both of which emerge as important regulatory pathways. These are indicative of a safeguard step that maintains the fidelity of the transcription process, becoming the ultimate mechanism mediating the protection of the breast conferred by full-term pregnancy
The proteolytic activity of MT4-MMP is required for its proangiogenic and pro-metastatic promoting effects

MT4-MMP expression in breast adenocarcinoma stimulates tumor growth and metastatic spreading to the lung. However whether these pro-tumorigenic and pro-metastatic effects of MT4-MMP are related to a proteolytic action is not known yet. Through site directed mutagenesis MT4-MMP has been inactivated in cancer cells through Glutamic acid 249 substitution by Alanine in the active site. Active MT4-MMP triggered an angiogenic switch at day 7 after tumor implantation and drastically accelerated subcutaneous tumor growth as well as lung colonization in RAG -/- mice. All these effects were abrogated upon MT4-MMP inactivation. In sharp contrast to most MMPs being primarily of stromal origin, we provide evidence that tumor-derived MT4-MMP, but not host-derived MT4-MMP contributes to angiogenesis. A genetic approach using MT4-MMP-deficient mice revealed that the status of MT4-MMP produced by host cells did not affect the angiogenic response. Despite of this tumor intrinsic feature, to exert its tumor promoting effect, MT4-MMP requires a permissive microenvironment. Indeed, tumor-derived MT4-MMP failed to circumvent the lack of an host angio-promoting factor such as lasminogen activator inhibitor (PAI-1). Overall, our study demonstrates the key contribution of MT4-MMP catalytic activity in the tumor compartment, at the interface with host cells. It identifies MT4-MMP as a key intrinsic tumor cell determinant that contributes to the elaboration of a permissive microenvironment for metastatic disseminationPeer reviewe
BMP‐2 inhibits tumor growth of human renal cell carcinoma and induces bone formation

Bone morphogenetic protein‐2 (BMP‐2), a member of the transforming growth factor superfamily, has been shown to have inhibitory effect on many tumor types. However, the effect of BMP‐2 on human renal cell carcinoma (RCC) is still unknown. We previously showed that BMP‐2 inhibits tumorigenicity of cancer stem cells in human osteosarcoma OS99‐1 cells. Our study investigates the effect of BMP‐2 on human RCC using ACHN and Caki‐2 cell lines. Three types of BMP receptors were found to be expressed in ACHN and Caki‐2 cells.  In vitro , BMP‐2 was found to inhibit the growth of ACHN and Caki‐2 cells. The antiproliferative effect seems to be due to cell cycle arrest in the G1 phase, which was revealed by flow cytometry analysis. Using reverse transcriptase polymerase chain reaction analysis, we demonstrated BMP‐2 upregulated osteogenic markers  Runx‐2  and  Collagen Type I  gene expression in ACHN and Caki‐2 cells. Treatment of ACHN and Caki‐2 cells with BMP‐2 induced a rapid phosphorylation of Smad1/5/8.  In vivo , all animals receiving low number of ACHN (1 × 10 4 ) and Caki‐2 (5 × 10 4 ) cells treated with 30 μg of BMP‐2 per animal showed limited tumor growth with significant bone formation, whereas untreated cells developed large tumor masses without bone formation in immunodeficient non‐obese diabetic (NOD)/severe combined immunodeficient (SCID) mice. These results suggest that BMP‐2 inhibits growth of RCC as well as causes induction of osseous bone formation. Further research is needed to determine the relationship between inhibition of cell proliferation and bone induction
Mice lacking epidermal PPARγ exhibit a marked augmentation in photocarcinogenesis associated with increased UVB-induced apoptosis, inflammation and barrier dysfunction

Recent studies suggest that peroxisome proliferator-activated receptor gamma (PPARγ) agonists may have cancer chemopreventive activity. Other studies have shown that loss of epidermal PPARγ results in enhanced chemical carcinogenesis in mice via unknown mechanisms. However, ultraviolet B (UVB) exposure represents the primary etiological agent for skin cancer formation and the role of PPARγ in photobiology and photocarcinogenesis is unknown. In previous studies, we demonstrated that UVB irradiation of cells results in the formation of oxidized glycerophosphocholines that exhibit PPARγ ligand activity. We therefore hypothesized that PPARγ would prove to be a chemopreventive target in photocarcinogenesis. We first showed that UVB irradiation of mouse skin causes generation of PPARγ agonist species in vivo. We then generated SKH-1 hairless, albino mice deficient in epidermal Pparg (Pparg-/-(epi)) using a cytokeratin 14 driven Cre-LoxP strategy. Using a chronic model of UVB photocarcinogenesis, we next showed that Pparg-/-(epi) mice exhibit an earlier onset of tumor formation, increased tumor burden and tumor progression. Increased tumor burden in Pparg-/-(epi) mice was accompanied by a significant increase in epidermal hyperplasia and p53 positive epidermal cells in surrounding skin lacking tumors. After acute UVB irradiation, Pparg-/-(epi) mice exhibited an augmentation of both UVB-induced Caspase 3/7 activity and inflammation. Increased apoptosis and inflammation was also observed after treatment with the PPARγ antagonist GW9662. With chronic UVB irradiation, Pparg-/-(epi) mice exhibited a sustained increase in erythema and transepidermal water loss relative to wildtype littermates. This suggests that PPARγ agonists could have possible chemopreventive activity in non-melanoma skin cancer