Home pesticide exposures and risk of childhood leukemia: Findings from the childhood leukemia international consortium Tập 137 Số 11 - Trang 2644-2663 - 2015
Helen D. Bailey, Claire Infante‐Rivard, Catherine Metayer, Jacqueline Clavel, Tracy Lightfoot, Peter Kaatsch, Eve Roman, Corrado Magnani, Logan G. Spector, Eleni Petridou, Elizabeth Milne, John D. Dockerty, Lucia Miligi, Bruce K. Armstrong, Jérémie Rudant, Lin Fritschi, Jill Simpson, Luoping Zhang, Roberto Rondelli, Margarita Baka, Laurent Orsi, Maria Moschovi, Alice Y. Kang, Joachim Schüz
Some previous studies have suggested that home pesticide exposure before birth and during a child's early years may increase the risk of childhood leukemia. To further investigate this, we pooled individual level data from 12 case–control studies in the Childhood Leukemia International Consortium. Exposure data were harmonized into compatible formats. Pooled analyses were undertaken using multivariable unconditional logistic regression. The odds ratio (ORs) for acute lymphoblastic leukemia (ALL) associated with any pesticide exposure shortly before conception, during pregnancy and after birth were 1.39 (95% confidence interval [CI]: 1.25, 1.55) (using 2,785 cases and 3,635 controls), 1.43 (95% CI: 1.32, 1.54) (5,055 cases and 7,370 controls) and 1.36 (95% CI: 1.23, 1.51) (4,162 cases and 5,179 controls), respectively. Corresponding ORs for risk of acute myeloid leukemia (AML) were 1.49 (95% CI: 1.02, 2.16) (173 cases and 1,789 controls), 1.55 (95% CI: 1.21, 1.99) (344 cases and 4,666 controls) and 1.08 (95% CI: 0.76, 1.53) (198 cases and 2,655 controls), respectively. There was little difference by type of pesticide used. The relative similarity in ORs between leukemia types, time periods and pesticide types may be explained by similar exposure patterns and effects across the time periods in ALL and AML, participants' exposure to multiple pesticides, or recall bias. Although some recall bias is likely, until a better study design can be found to investigate the associations between home pesticide use and childhood leukemia in an equally large sample, it would appear prudent to limit the use of home pesticides before and during pregnancy, and during childhood.
Enhanced inhibitive effects of combination of rofecoxib and octreotide on the growth of human gastric cancer Tập 112 Số 3 - Trang 470-474 - 2004
Chengwei Tang, Liu Chun-lun, Xuchun Zhou, Chunhui Wang
AbstractOur previous studies indicated that cyclooxygenase‐2 inhibitor or octreotide could suppress the proliferation of gastric adenocarcinoma in vitro or in vivo. The present study was aimed to find whether rofecoxib combined with octreotide could enhance the inhibitive effects on the growth of gastric cancer. The effect of rofecoxib or octreotide on proliferation of gastric cancer cell line was determined by 3H‐thymidine ribotide incorporation. The TdT‐mediated dUTP nick end‐labeling assay was used to detect the apopotosis. To determine their synergic antineoplastic effects, the interaction between rofecoxib and octreotide on SGC‐7901 cell was evaluated by the median effect plot. After orthotopical implantion of xenografts of human gastric cancer in stomach, nude mice were given rofecoxib plus octreotide for 8 weeks. Cyclooxygenase‐2 in gastric cancer tissues was measured by immunohistochemistry. Combination of rofecoxib and octreotide presented synergistic effect (combination index < 1) in the majority of responses. The inhibitory rate for xenografts in nude mice was 89.7% in rofecoxib group. Combination of rofecoxib and octreotide enhanced inhibitory rate to 98.8%. The combination greatly increased the apoptotic index (78.20% ± 6.45%) of the xenografts as compared with that of using rofecoxib alone (46.60% ± 3.42%); the difference was very significant (p < 0.001). Rofecoxib could inhibit the activity of cyclooxygenase‐2 in the tissue of gastric adenocarcinomas of nude mice. Our results indicate that combination of rofecoxib and octreotide significantly enhances the antiproliferative effect in gastric adenocarcinoma, which might have potential therapeutic value. © 2004 Wiley‐Liss, Inc.
Polymorphisms and haplotype structures in genes for transforming growth factor β1 and its receptors in familial and unselected breast cancers Tập 112 Số 1 - Trang 94-99 - 2004
Qianren Jin, Kari Hemminki, Ewa Grzybowska, Ruediger Klaes, Magnus Söderberg, Helena Zientek, J. Rogozińska-Szczepka, B. Utracka-Hutka, Jolanta Pamuła‐Piłat, Wioletta Pękala, Asta Försti
AbstractAlterations in TGF‐β signaling appear to be associated with an altered risk of developing cancer, including breast cancer. We carried out a case‐control study on 8 polymorphisms, including 5 in the TGF‐β1 gene (G‐800A, C‐509T, Leu10→Pro, Arg25→Pro and Thr263→Ile), a polyalanine polymorphism (9A→6A) in the TGF‐βRI gene and 2 (G‐875A and A‐364G) in the TGF‐βRII gene, using samples from 2 different populations, Polish familial and Finnish unselected breast cancer cases, together with ethnically and geographically matched controls. Additionally, familial breast cancer cases with respective controls from Sweden and Germany were studied in the Leu10→Pro polymorphism, making the total number of familial cases 659. Allele, genotype and haplotype analysis on the TGF‐β1 gene as well as an analysis of the combinations of genotypes of the TGF‐β1 and its receptor genes in each individual were performed. Population differences in the allele and genotype distributions were found from 5 of the polymorphisms and 3 common haplotypes from the TGF‐β1 gene between the Finnish and other populations. However, no statistically significant difference between the breast cancer and healthy control groups was found for any of the 8 polymorphisms nor did the haplotype or genotype combination analysis reach statistical significance. Thus, none of the studied polymorphisms from the TGF‐β1 and its receptor genes was found to influence significantly susceptibility to breast cancer. The possible contribution of 6A/6A homozygosity in the TGF‐βRI gene to breast cancer needs to be confirmed in an independent study. © 2004 Wiley‐Liss, Inc.
Protein kinase B modulates the sensitivity of human neuroblastoma cells to insulin‐like growth factor receptor inhibition Tập 119 Số 11 - Trang 2527-2538 - 2006
Ana Guerreiro Stücklin, Danielle Boller, Tarek Shalaby, Michael Grotzer, Alexandre Arcaro
AbstractThe potential of the novel insulin‐like growth factor receptor (IGF‐IR) inhibitor NVP‐AEW541 as an antiproliferative agent in human neuroblastoma was investigated. Proliferation of a panel of neuroblastoma cell lines was inhibited by NVP‐AEW541 with IC50 values ranging from 0.15 to 5 μM. Experiments using an IGF‐IR neutralizing antibody confirmed that the IGF‐IR was essential to support growth of neuroblastoma cell lines. The expression levels of the IGF‐IR in individual neuroblastoma cell lines did not correlate with the sensitivities to NVP‐AEW541, while coexpression of the IGF‐IR and the insulin receptor (IR) correlated with lower sensitivity to the inhibitor in some cell lines. Intriguingly, high levels of activation of Akt/protein kinase B (PKB) and phosphorylation of the ribosomal S6 protein were observed in neuroblastoma cell lines with decreased sensitivities to NVP‐AEW541. Inhibition of Akt/PKB activity restored the sensitivity of neuroblastoma cells to the IGF‐IR inhibitor. Transfection of neuroblastoma cells with activated Akt or ribosomal protein S6 kinase (S6K) decreased the sensitivity of the cells to NVP‐AEW541. IGF‐I‐stimulated proliferation of neuroblastoma cell lines was completely blocked by NVP‐AEW541, or by a combination of an inhibitor of phosphoinositide 3‐kinase and rapamycin. In addition to its antiproliferative effects, NVP‐AEW541 sensitized neuroblastoma cells to cisplatin‐induced apoptosis. Together, our data demonstrate that NVP‐AEW541 in combination with Akt/PKB inhibitors or chemotherapeutic agents may represent a novel approach to target human neuroblastoma cell proliferation. © 2006 Wiley‐Liss, Inc.
A dual‐specific anti‐<scp>IGF‐1/IGF‐2</scp> human monoclonal antibody alone and in combination with temsirolimus for therapy of neuroblastoma Tập 137 Số 9 - Trang 2243-2252 - 2015
Qi Zhao, Hoa Tran, Dimiter S. Dimitrov, Nai‐Kong V. Cheung
The insulin‐like growth factors (IGFs), IGF‐1 and IGF‐2, have been implicated in the growth, survival and metastasis of a broad range of malignancies including pediatric tumors. They bind to the IGF receptor type 1 (IGF‐1R) and the insulin receptor (IR) which are overexpressed in many types of solid malignancies. Activation of the IR by IGF‐2 results in increased survival of tumor cells. We have previously identified a novel human monoclonal antibody, m708.5, which binds with high (pM) affinity to both human IGF‐1 and IGF‐2, and potently inhibits phosphorylation of the IGF‐1R and the IR in tumor cells. m708.5 exhibited strong antitumor activity as a single agent against most cell lines derived from neuroblastoma, Ewing family of tumor, rhabdomyosarcoma and osteosarcoma. When tested in neuroblastoma cell lines, it showed strong synergy with temsirolimus and synergy with chemotherapeutic agents in vitro. In xenograft models, the combination of m708.5 and temsirolimus significantly inhibited neuroblastoma growth and prolonged mouse survival. Taken together, these results support the clinical development of m708.5 for pediatric solid tumors with potential for synergy with chemotherapy and mTOR inhibitors.
Increased expression of fatty acid synthase and progesterone receptor in early steps of human mammary carcinogenesis Tập 120 Số 2 - Trang 224-229 - 2007
Majida Esslimani‐Sahla, Simon Thézenas, Thierry Chardès, Andrew Kramar, Roselyne Lavaill, Dany Chalbos, Henri Rochefort
AbstractProgestins increase the risk of breast cancer in the hormone therapy of menopause, and progesterone receptor‐induced fatty acid synthase (FAS) is a potential therapeutical target of breast cancer. In a first attempt to specify in which lesions at risk of breast cancer progestins might be acting, we have compared the progesterone receptor (PR) and FAS expression in preinvasive breast lesions and in adjacent “normal” mammary glands. We used archive paraffin‐embedded tissues from 116 patients, with 164 lesions of increasing histological risk from nonproliferative “benign” breast disease (BBD) to in situ breast carcinomas. Immunostaining using our FAS antibody and a PR antibody from Dako was quantified as continuous variables by computer‐assisted image analysis. FAS level increased (p < 10−3 by the Kruskall–Wallis test) in all lesions, starting from nonproliferative BBD, and was maximal in in situ carcinoma. The % of PR‐positive cells increased from nonproliferative BBD and was higher in proliferative atypia (p < 10−3). It was very low in high‐grade DCIS corresponding to a likely different carcinogenesis pathway. There was a trend for a positive correlation between FAS and PR in normal glands. However, the 2 markers increased independently in BBD and were negatively correlated in in situ carcinomas. FAS and PR were positively correlated with Ki67 in BBD. The increased PR level in premalignant steps of mammary carcinogenesis suggests an early increased responsiveness to progestins. The increased FAS expression, in lesions parallel to their increased breast cancer risk, suggests further studies to develop new markers of high‐risk lesions and to prevent breast cancer. © 2006 Wiley‐Liss, Inc.
Retracted: Exosomal circRNA derived from gastric tumor promotes white adipose browning by targeting the miR‐133/PRDM16 pathway Tập 144 Số 10 - Trang 2501-2515 - 2019
Haiyang Zhang, Lei Zhu, Ming Bai, Ying Liu, Zhan Yang, Ting Deng, Haiou Yang, Wu Sun, Xinyi Wang, Kegan Zhu, Qian Fan, Jialu Li, Guoguang Ying, Yi Ba
Cancer‐related cachexia is a metabolic syndrome characterized by a wasting disorder of adipose and skeletal muscle and is accompanied by body weight loss and systemic inflammation. The treatment options for cancer cachexia are limited, and the molecular mechanism remains poorly understood. Circular RNAs (circRNAs) are a novel family of endogenous noncoding RNAs that have been proposed to regulate gene expression in mammals. Exosomes are small vesicles derived from cells, and recent studies have shown that circRNAs are stable in exosomes. However, little is known about the biological role of circRNAs in exosomes. In our study, we showed that circRNAs in plasma exosomes have specific expression features in gastric cancer (GC), and ciRS‐133 is linked with the browning of white adipose tissue (WAT) in GC patients. Exosomes derived from GC cells deliver ciRS‐133 into preadipocytes, promoting the differentiation of preadipocytes into brown‐like cells by activating PRDM16 and suppressing miR‐133. Moreover, knockdown of ciRS‐133 reduced cancer cachexia in tumor‐implanted mice, decreasing oxygen consumption and heat production. Thus, exosome‐delivered circRNAs are involved in WAT browning and play a key role in cancer‐associated cachexia.
Three molecular pathways model colorectal carcinogenesis in <scp>L</scp>ynch syndrome Tập 143 Số 1 - Trang 139-150 - 2018
Aysel Ahadova, Richard Gallon, Johannes Gebert, Alexej Ballhausen, Volker Endris, Martina Kirchner, Albrecht Stenzinger, John Burn, Magnus von Knebel Doeberitz, Hendrik Bläker, Matthias Kloor
Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR‐deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR‐deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR‐deficient cells by chemoprevention or vaccines against MMR deficiency‐induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome.
Prevalence of human papillomavirus and cervical intraepithelial neoplasia in China: A pooled analysis of 17 population‐based studies Tập 131 Số 12 - Trang 2929-2938 - 2012
Fanghui Zhao, Adam K. Lewkowitz, Shangying Hu, Feng Chen, Long‐Yu Li, Qing‐Ming Zhang, Rui‐Fang Wu, Changqing Li, Lihui Wei, Aidi Xu, Wen‐Hua Zhang, Qin‐Jing Pan, Qian Zhang, Jerome L. Belinson, John W. Sellors, Jennifer S. Smith, You‐Lin Qiao, Silvia Franceschi
AbstractHigh‐risk (HR) human papillomavirus (HPV) prevalence has been shown to correlate well with cervical cancer incidence rates. Our study aimed to estimate the prevalence of HR‐HPV and cervical intraepithelial neoplasia (CIN) in China and indirectly informs on the cervical cancer burden in the country. A total of 30,207 women from 17 population‐based studies throughout China were included. All women received HPV DNA testing (HC2, Qiagen, Gaithersburg, MD), visual inspection with acetic acid and liquid‐based cytology. Women positive for any test received colposcopy‐directed or four‐quadrant biopsies. A total of 29,579 women had HR‐HPV testing results, of whom 28,761 had biopsy confirmed (9,019, 31.4%) or assumed (19,742, 68.6%) final diagnosis. Overall crude HR‐HPV prevalence was 17.7%. HR‐HPV prevalence was similar in rural and urban areas but showed dips in different age groups: at age 25–29 (11.3%) in rural and at age 35–39 (11.3%) in urban women. In rural and urban women, age‐standardized CIN2 prevalence was 1.5% [95% confidence interval (CI): 1.4–1.6%] and 0.7% (95% CI: 0.7–0.8%) and CIN3+ prevalence was 1.2% (95% CI: 1.2–1.3%) and 0.6% (95% CI: 0.5–0.7%), respectively. Prevalence of CIN3+ as a percentage of either all women or HR‐HPV‐positive women steadily increased with age, peaking in 45‐ to 49‐year‐old women. High prevalence of HR‐HPV and CIN3+ was detected in both rural and urban China. The steady rise of CIN3+ up to the age group of 45–49 is attributable to lack of lesion removal through screening. Our findings document the inadequacy of current screening in China while indirectly raising the possibility that the cervical cancer burden in China is underreported.
Impact of multiple HPV infection on response to treatment and survival in patients receiving radical radiotherapy for cervical cancer Tập 102 Số 3 - Trang 237-243 - 2002
Barbara Bachtiary, Andreas Obermair, Bettina Dreier, Peter Birner, G. Breitenecker, Tomas‐Hendrik Knocke, Edgar Selzer, Richard Pötter
AbstractTo obtain information on the incidence and the clinical significance of infection with various types of the human papillomavirus (HPV) in cancer of the uterine cervix, we retrospectively examined the HPV status of 106 patients who had received radical radiotherapy for cervical cancer stages IB to IIIB. DNA was extracted from formalin‐fixed, paraffin‐embedded biopsies and PCR was carried out to identify HPV types 16, 18, 31, 35, 33 and 45. To detect additional HPV types, consensus PCR products were cloned and sequenced. A catalyzed signal‐amplified colorimetric in situ hybridization was carried out in 84 of 106 specimens as a positive control. Response to therapy, progression‐free survival (PFS) and cervical cancer‐specific survival (CCSS) were the statistical endpoints. Survival analysis was carried out using univariate and multivariate analysis (Cox regression). Ninety‐six patients (90.6%) were HPV‐positive and 42/96 (43.7%) were positive for multiple HPV types. Eight patients had persistent disease after radiotherapy. From these 8 patients, 7 were infected with multiple HPV types and only 1 patient had an infection with a single HPV type. After a median follow up period of 50 months, patients with multiple HPV infection had a significantly shorter PFS and CCSS compared to those with single HPV infection (24.8% and 34.9% vs. 64% and 60.8%, Log rank, p < 0.01 and 0.04). In multivariate analysis, the presence of multiple HPV types (RR 1.9), node status (RR 2.3), tumor size (RR 3.2) and histologic type (RR 4.8) were independent prognostic factors of CCSS. Our results demonstrate that the presence of multiple HPV types is associated with poor response and with reduced survival in cervical cancer patients who receive radiotherapy as the primary treatment. © 2002 Wiley‐Liss, Inc.