pinecone/core-2020-05-10-deduplication huggingface dataset:
Emergence of potential biomarkers of response to anti-angiogenic anti-tumour agents.

Anti-angiogenic agents targeting tumour vasculature have an established place in clinical practice, and new data are constantly emerging. However, despite rapid clinical uptake, a very large number of questions regarding these agents remain unanswered. One of the main hurdles in clinical practice is lack of accurate and feasible ways of assessing response to drug beyond tumour reduction on conventional imaging. This review summarises recent developments in the field of biomarkers of response to anti-VEGF drugs
Therapeutic applications of bioactive sphingolipids in hematological malignancies

Sphingolipids are sphingosine-based lipid molecules that have important functions in cellular signal transduction and in a variety of cellular processes including proliferation, differentiation, programmed cell death (apoptosis) and responses to stressful conditions. Ceramides, dihydroceramide, sphingosine and sphingosine-1-phosphate are examples of those bioactive sphingolipids. They have a major impact on determination of the cell fate by contributing to the cell survival or cell death through apoptosis. Despite the number of carbon atoms in the fatty acid chain changes the physiological role; ceramides generally exert suppressive roles on the cell proliferation. There have been several enzymes identified in this pathway that are responsible for the conversion of ceramide into other sphingolipid derivatives. Those derivatives also have differential roles on those cellular processes. Sphingosine-1-phosphate is an example of such sphingolipid derivatives which has antiapoptotic effects. As they have significant impacts particularly on the cell death and survival, bioactive sphingolipids have a great potential to be targets in cancer therapy. Increasing number of studies indicates that sphingolipid derivatives are important in the progression of hematological malignancies, and they are also involved in the resistance to current chemotherapeutic options. This review compiles the current knowledge in this area for enlightening the therapeutic potentials of bioactive sphingolipids in various leukemias. © 2010 UICC
Allergy and glioma risk: Test of association by genotype

Although epidemiological studies have suggested an association between atopy and glioma risk, these observations have been based on self-reporting of allergic conditions raising the possibility that associations may be noncausal and arise as a consequence of bias, reverse causation or other artifacts. Genetic information provides an alternative approach to investigate the relationship avoiding such biases. We analyzed 1,878 glioma cases and 3,670 controls for variants at 2q12, 5q12.1, 11q13 and 17q21 that are associated with asthma or eczema risk at p < 5.0 × 10−7. The SNP rs7216389, which tags the 3′ flanking region of ORMDL3 at 17q21 and has been associated with childhood asthma, was correlated with increased glioma risk (OR = 1.10; 95% CI: 1.01–1.19). These data provide evidence for a correlation between asthma susceptibility and glioma risk and illustrate the value of using genetics as an investigative tool for developing etiological hypotheses
Micro-RNA-21 regulates TGF-β-induced myofibroblast differentiation by targeting PDCD4 in tumor-stroma interaction

Transforming growth factor-β1 (TGF-β1) induces stromal fibroblast-to-myofibroblast transdifferentiation in the tumor-stroma interactive microenvironment via modulation of multiple phenotypic and functional genes, which plays a critical role in tumor progression. Up to now, the involvement of micro-RNAs (miRNAs) and their roles in TGF-β1-induced myofibroblast differentiation in tumor-stroma interaction are unclear. Using quantitative real-time RT-PCR, we demonstrated that the expression of micro-RNA-21 (miR-21) was upregulated in activated fibroblasts after treatment with TGF-β1 or conditioned medium from cancer cells. To determine the potential roles of miR-21 in TGF-β1-mediated gene regulation during myofibroblast conversion, we showed that miR-21 expression was downregulated by miR-21 inhibitor and upregulated by miR-21 mimic. Interestingly, downregulation of miR-21 with the inhibitor effectively inhibited TGF-β1-induced myofibroblast differentiation while upregulation of miR-21 with a mimic significantly promoted myofibroblast differentiation. We further demonstrated that MiR-21 directly targeted and downregulated programmed cell death 4 (PDCD4) gene, which in turn acted as a negative regulator of several phenotypic and functional genes of myofibroblasts. Taken together, these results suggested that miR-21 participated in TGF-β1-induced myofibroblast transdifferentiation in cancer stroma by targeting PDCD4.Griffith Health, School of Medical ScienceFull Tex
Association between melanoma thickness, clinical skin examination and socioeconomic status: Results of a large population-based study

Survival from melanoma is inversely related to tumour thickness and is less favorable for those in lower socioeconomic (SES) strata. Reasons for this are unclear but may relate to a lower prevalence of skin screening. Our aim was to examine the association between melanoma thickness, individual-level SES and clinical skin examination (CSE) using a population-based case-control study. Cases were Queensland (Australia) residents aged 20–75 years with a histologically confirmed first primary invasive cutaneous melanoma diagnosed between January 2000 and December 2003. Telephone interviews were completed by 3,762 cases (77.7%) and 3,824 (50.4%) controls. Thickness was dichotomized to thin (≤2 mm) and thick (>2 mm). Compared with controls, the risk of thick melanoma was significantly increased among men [relative risk ratio (RRR) = 1.56, 95% CI = 1.22–2.00], older participants (RRR = 1.76, 95% CI = 1.10–2.82), those educated to primary level (RRR = 1.70, 95% CI = 1.08–2.66), not married/living as married (RRR = 1.47, 95% CI = 1.15–1.88), retired (RRR = 1.39, 95% CI = 1.01–1.94) and not having a CSE in past 3 years (RRR = 1.45, 95% CI = 1.12–1.86). There was a significant trend to increasing prevalence of CSE with higher education (p < 0.01) and the benefit of CSE in reducing the risk of thick melanoma was most pronounced among that subgroup. There were no significant associations between cases with thin melanoma and controls. Melanoma thickness at presentation is significantly associated with educational level, other measures of SES and absence of CSE. Public health education efforts should focus on identifying new avenues that specifically target those subgroups of the population who are at increased risk of being diagnosed with thick melanoma.Full Tex
The novel histone deacetylase inhibitor, AR-42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells

Multiple myeloma (MM) remains incurable with current therapy, indicating the need for continued development of novel therapeutic agents. We evaluated the activity of a novel phenylbutyrate-derived histone deacetylase inhibitor, AR-42, in primary human myeloma cells and cell lines. AR-42 was cytotoxic to MM cells at a mean LC(50) of 0.18 ± 0.06 μmol/l at 48 hr and induced apoptosis with cleavage of caspases 8, 9 and 3, with cell death largely prevented by caspase inhibition. AR-42 downregulated the expression of gp130 and inhibited activation of STAT3, with minimal effects on the PI3K/Akt and MAPK pathways, indicating a predominant effect on the gp130/STAT-3 pathway. AR-42 also inhibited interleukin (IL)-6-induced STAT3 activation, which could not be overcome by exogenous IL-6. AR-42 also downregulated the expression of STAT3-regulated targets, including Bcl-xL and cyclin D1. Overexpression of Bcl-xL by a lentivirus construct partly protected against cell death induced by AR-42. The cyclin dependent kinase inhibitors, p16 and p21, were also significantly induced by AR-42, which together with a decrease in cyclin D1, resulted in G(1) and G(2) cell cycle arrest. In conclusion, AR-42 has potent cytotoxicity against MM cells mainly through gp130/STAT-3 pathway. The results provide rationale for clinical investigation of AR-42 in MM
Reactive species and DNA damage in chronic inflammation: Reconciling chemical mechanisms and biological fates

Chronic inflammation has long been recognized as a risk factor for many human cancers. One mechanistic link between inflammation and cancer involves the generation of nitric oxide, superoxide and other reactive oxygen and nitrogen species by macrophages and neutrophils that infiltrate sites of inflammation. Although pathologically high levels of these reactive species cause damage to biological molecules, including DNA, nitric oxide at lower levels plays important physiological roles in cell signaling and apoptosis. This raises the question of inflammation-induced imbalances in physiological and pathological pathways mediated by chemical mediators of inflammation. At pathological levels, the damage sustained by nucleic acids represents the full spectrum of chemistries and likely plays an important role in carcinogenesis. This suggests that DNA damage products could serve as biomarkers of inflammation and oxidative stress in clinically accessible compartments such as blood and urine. However, recent studies of the biotransformation of DNA damage products before excretion point to a weakness in our understanding of the biological fates of the DNA lesions and thus to a limitation in the use of DNA lesions as biomarkers. This review will address these and other issues surrounding inflammation-mediated DNA damage on the road to cancer.National Institute of Environmental Health Sciences (CA116318)National Institute of Environmental Health Sciences (CA103146)National Institute of Environmental Health Sciences (CA026731)National Institute of Environmental Health Sciences (ES016450)National Institute of Environmental Health Sciences (ES002109)National Institute of Environmental Health Sciences (ES017010)National Cancer Institute (U.S.)National Science Foundation (U.S.) (grant no. CHE-1019990)Singapore-MIT Alliance for Research and TechnologyMassachusetts Institute of Technology (Westaway Fund
Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells

Identification of cancer stem cells is crucial for advancing cancer biology and therapy. Several markers including CD24, CD44, CD117, CD133, the G subfamily of ATP‐binding cassette transporters (ABCG), epithelial specific antigen (ESA) and aldehyde dehydrogenase (ALDH) are used to identify and investigate human epithelial cancer stem cells in the literature. We have now systemically analyzed and compared the expression of these markers in fresh ovarian epithelial carcinomas. Although the expression levels of these markers were unexpectedly variable and partially overlapping in fresh ovarian cancer cells from different donors, we reliably detected important levels of CD133 and ALDH in the majority of fresh ovarian cancer. Furthermore, most of these stem cell markers including CD133 and ALDH were gradually lost following  in vitro  passage of primary tumor cells. However, the expression of ALDH and CD133, but not CD24, CD44 and CD117, could be partially rescued by the  in vitro  serum‐free and sphere cultures and by the  in vivo  passage in the immune‐deficient xenografts. ALDH +  and CD133 +  cells formed three‐dimensional spheres more efficiently than their negative counterparts. These sphere‐forming cells expressed high levels of stem cell core gene transcripts and could be expanded and form additional spheres in long‐term culture. ALDH + , CD133 +  and ALDH + CD133 +  cells from fresh tumors developed larger tumors more rapidly than their negative counterparts. This property was preserved in the xenografted tumors. Altogether, the data suggest that ALDH +  and CD133 +  cells are enriched with ovarian cancer‐initiating (stem) cells and that ALDH and CD133 may be widely used as reliable markers to investigate ovarian cancer stem cell biology
Time trends and latitudinal differences in melanoma thickness distribution in Australia, 1990-2006

This study investigated time trends and latitude differentials in the thickness distributions of invasive melanomas diagnosed in Australia between 1990 and 2006 using data from population-based cancer registries. Trends in incidence rates were calculated by sex, age group, thickness, year at diagnosis and latitude. For thin (<1.00mm) melanomas the increase was very pronounced during the early 1990s (1990-1996, annual percentage change and 95% confidence interval: males +5.6(+3.5,+7.7); females +4.1(+1.7,+6.5), but then incidence rates became stable among both males (+0.6(-0.1,+1.4)) and females (-0.0(-0.9,+0.9)) of all ages between 1996 and 2006. In contrast, incidence of thick (>4.00 mm) melanomas continued to increase over the entire period (males +2.6(+1.9,+3.4); females +1.6(+0.6,+2.6)). Recent reductions in the incidence of thin melanomas were observed among young (<50 years) males and females, contrasted by an increase in thin melanomas among older people, and increases in thick melanomas among most age groups for males and elderly (75+) females. A strong latitude gradient in incidence rates was observed, with rates being highest in northern, more tropical areas and lowest in the most southern regions. However, the magnitude of the increase in thick melanomas was most pronounced in southern parts of Australia. The observed trends in thin melanomas can most likely be attributed to the impact of early detection and skin awareness campaigns. However, these efforts have not impacted on the continued increase in the incidence of thick melanomas, although some increase may be due to earlier detection of metastasising melanomas. This highlights the need for continued vigilance in early detection processes.Griffith Health, School of Applied PsychologyFull Tex
Vitamin D receptor polymorphisms in patients with cutaneous melanoma

The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38  VDR  gene single nucleotide polymorphisms (SNPs) in a large international multicenter population‐based case‐control study of melanoma. Buccal DNAs were obtained from 1,207 people with incident multiple primary melanoma and 2,469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, haplotype tagging SNPs with ≥10% minor allele frequency in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3′ gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25 to 33% for six polymorphisms: rs10875712 (odds ratios [OR] 1.28; 95% confidence interval (CI), 1.01–1.62), rs4760674 (OR 1.33; 95% CI, 1.06–1.67), rs7139166 (OR 1.26; 95%CI, 1.02–1.56), rs4516035 (OR 1.25; 95%CI, 1.01–1.55), rs11168287 (OR 1.27; 95%CI, 1.03–1.57) and rs1544410 (OR 1.30; 95%CI, 1.04–1.63); for two polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65–1.02) and rs7965281 (OR, 0.78; 95%CI, 0.62–0.99). We recognize the potential false positive findings because of multiple comparisons; however, the eight significant SNPs in our study outnumbered the two significant tests expected to occur by chance. The VDR may play a role in melanomagenesis
The effect of estrogen  vs.  combined estrogen‐progestogen therapy on the risk of colorectal cancer

Studies suggest that estrogen therapy (ET) and combined estrogen‐progestogen therapy (EPT) may have different associations with colorectal cancer (CRC) risk, but data are conflicting. Prior meta‐analyses did not distinguish between ET and EPT. We conducted a meta‐analysis to summarize the relative risks (RR) of CRC due to ET versus EPT among peri‐ or postmenopausal women. From a total of 2,661 articles, four randomized controlled trials, eight cohort and eight case‐control studies were included. Variables assessed included study characteristics, duration and recency of menopausal hormone therapy (HT) use, method of assessment of HT use, outcome definition and its ascertainment method. RRs were synthesized by random‐effects models. We found that EPT ever use was associated with a decreased risk of CRC (RR 0.74, 95% CI 0.68‐0.81), and so was ET ever use (RR 0.79, 95% CI 0.69‐0.91). While current use of ET was associated with a significantly reduced risk of CRC (RR 0.70, 95% CI 0.57‐0.85), former use was not (RR 0.86, 95%CI 0.67‐1.11). Recency did not significantly modify the association between EPT and CRC risk. EPT former use was associated with a lower RR of CRC compared to ET former use ( p  = 0.008) but no such difference was observed between EPT and ET current use ( p  = 0.12). Overall, we found consistent evidence supporting the association between EPT and CRC risk reduction, regardless of recency. While literature for the association between ET and CRC risk is heterogeneous, our analyses suggest only current use of ET is associated with a decreased CRC risk
Circulating estrogens and progesterone during primiparous pregnancies and risk of maternal breast cancer.

Pregnancy reduces maternal risk of breast cancer in the long term, but the biological determinants of the protection are unknown. Animal experiments suggest that estrogens and progesterone could be involved, but direct human evidence is scant. A case-control study (536 cases and 1,049 controls) was nested within the Finnish Maternity Cohort. Eligible were primiparous women who delivered at term a singleton offspring before age 40. For each case, two individually matched controls by age (±6 months) and date of sampling (±3 months) were selected. Estradiol, estrone and progesterone in first-trimester serum were measured by high-performance liquid chromatography tandem mass spectrometry and sex-hormone binding globulin (SHBG) by immunoassay. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. In the whole study population there was no association of breast cancer with any of the studied hormones. In analyses stratified by age at diagnosis, however, estradiol concentrations were positively associated with risk of breast cancer before age 40 (upper quartile OR, 1.81; CI, 1.08-3.06), but inversely associated with risk in women who were diagnosed ≥age 40 (upper quartile OR, 0.64; CI, 0.40-1.04), p(interaction) 0.004. Risk estimates for estrone mirrored those for estradiol but were less pronounced. Progesterone was not associated with risk of subsequent breast cancer. Our results provide initial evidence that concentrations of estrogens during the early parts of a primiparous pregnancy are associated with maternal risk of breast cancer and suggest that the effect may differ for tumors diagnosed before and after age 40
Cervical cancer : incidence, screening and prognosis among immigrant women in Sweden

Immigrant studies may help further our understanding of the aetiology of cervical cancer and improve its prevention. The overall aim of this thesis is to study the risk of cervical cancer among immigrant women in Sweden, their cervical screening attendance and their prognosis after cervical cancer diagnosis. Quantitative cohort study designs using data from population-based registers were carried out and analysed using Poisson regression and Cox proportional hazard models. A quantitative explorative design was used to analyse the results of focus group discussions (FGDs) according to the principles of content analysis.
Compared to Swedish-born women, immigrant women in Sweden had a higher relative risk of invasive cervical cancer, particularly women from Denmark, Norway and Central America; the opposite was true for immigrant women from Eastern Africa and South Central Asia. Moreover, age at immigration and follow-up time were important effect modifiers for the risk of cervical cancer among immigrant women (Study I). Average cervical screening attendance was 62% and 49% among Swedish-born and immigrant women, respectively, and was lowest among women who immigrated at older ages. Adherence to recommended screening intervals is very effective in preventing cervical cancer (Study II). The qualitative study using FGDs revealed a complex rationale for postponing cervical screening that included aspects related to immigration itself, including competing needs, organisational and structural factors, and differences in mentality (Study III). Non-Nordic immigrant women had a slightly lower risk of dying from cervical cancer than Swedish-born women. Both Swedish-born and immigrant women with symptomatic cervical cancer showed a 3 to 4-fold excess mortality compared to screening-detected cases. Both immigrant and Swedish-born women with low socioeconomic status had an excess risk of dying from cervical cancer (Study IV).
In conclusion, these results suggest a need for targeted prevention both among Swedish-born and immigrant women with low socioeconomic status and immigrant women at high-risk for cervical cancer, particularly those from Denmark, Norway and Central America, and specifically women who immigrate at older ages, during the first 10 years after their arrival. The results on cervical cancer prognosis indicate that there is equal access to health care in Sweden, irrespective of country of birth. The rationale of immigrant women in FGDs to postpone cervical screening reveals an opportunity to motivate these women to attend
Dietary lignan and proanthocyanidin consumption and colorectal adenoma recurrence in the Polyp Prevention Trial

This is the publisher’s final pdf. The published article is copyrighted by Wiley and can be found at: http://onlinelibrary.wiley.com/.Lignans and proanthocyanidins are plant polyphenols that have shown protective properties against colorectal neoplasms in some human studies. Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to prospectively evaluate the association between lignan and proanthocyanidin intake, estimated from databases linked to a food frequency questionnaire, and adenoma recurrence in 1,859 participants of the Polyp Prevention Trial. Overall, individual or total lignans or proanthocyanidins were not associated with colorectal adenoma recurrence. However, in sex-specific analyses, total lignan intake was positively associated with any adenoma recurrence in women (highest vs. lowest lignan intake quartile OR = 2.07, 95% CI: 1.223.52, p trend = 0.004) but not in men (p interaction = 0.04). To conclude, dietary lignan and proanthocyanidin consumption were not generally related to colorectal adenoma recurrence; however, high lignan intake may increase the risk of adenoma recurrence in women