pinecone/core-2020-05-10-deduplication huggingface dataset:
Novel Tumor Suppressor Gene Candidates in Experimental Endometrial Carcinoma - From Cytogenetic to Molecular Analysis

Endometrial carcinoma (EC) is the most common form of gynecological malignancy, ranking fourth in incidence among tumors diagnosed in women. As is the case with other complex diseases, detailed analyses of the underlying mechanisms of cancer are difficult, due mainly to the genetic heterogeneity of the human population and differences in the environment and lifestyle of individuals. In this sense, analysis in animal models may serve as a valuable complement. The inbred BDII rat strain is genetically prone to spontaneous hormone-related EC and it has been used as a powerful model to investigate molecular alterations in this tumor type. BDII female rats were crossed with males from two non-susceptible rat strains and tumors were developed in a significant fraction of the progeny. We subjected a subset of BDII rat tumors to detailed analysis based on the molecular data used for the classification of human ECs. Our analysis revealed that this tumor model can be related to higher grade human type I ECs, i.e. a subgroup of ECs that constitutes more than 80% of this tumor type in humans. 
Earlier work using comparative genome hybridization (CGH) revealed that rat chromosome 10 (RNO10) was frequently involved in cytogenetic aberrations in BDII rat tumors. To identify the potential target region(s)/gene(s) for these changes, we subjected a panel of rat ECs to allelic imbalance (AI) analysis. Four distinct regions of recurrent AI were identified. By deriving evolutionary tree models based on AI data, we demonstrated that one of these AI regions (located adjacent to Tp53) was close to the root in the derived onco-tree models, indicating that this segment might harbor early important events. In combined FISH, chromosome paint, gene expression and gene sequencing analyses, we found that, instead of Tp53, the main selection target was a region close and distal to Tp53. We developed a detailed deletion map of this area and substantially narrowed down the size of the candidate region. We then subjected all 19 genes located within this segment to qPCR analysis, followed by statistical analysis of the results, and thus identified the Hic1, Skip and Myo1c genes as potential target(s). By subjecting these genes to DNA sequencing, analysis of protein expression and of epigenetic silencing, we ruled out Hic1 and confirmed Skip and Myo1c as the candidates. Interestingly, it appears that Skip and Myo1c perform overlapping roles in PI 3-kinase/Akt signaling, which is known to have implications for the survival and growth of cancer cells. In conclusion, starting from cytogenetic findings and applying a candidate gene approach, we introduced two attractive candidate genes within the independent region of tumor suppressor activity distal to Tp53
Family history of cancer in children with acute leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma: the ESCALE study (SFCE).

International audienceThe role of a family history of cancer in the etiology of childhood hematopoietic malignancies was investigated using the data from the ESCALE study. ESCALE, a population-based case-control study, was carried out in France over the period, 2003-2004. A total of 773 cases of acute leukemia (AL), 130 of Hodgkin's lymphoma (HL), 163 of non-Hodgkin's lymphoma (NHL) and 1,681 population-based controls were included. The controls were randomly selected from the French population and were frequency matched with the cases on age and gender. Cancer history in first- and second-degree relatives was reported by the mothers in a structured telephone questionnaire that was the same for the cases and controls. Odds ratios (ORs) were estimated using an unconditional regression model taking into account the stratification variables and potential confounders. A family history of cancer was associated with an increased risk of HL (OR = 1.5 [1.0-2.2]) and NHL (OR = 1.8 [1.3-2.5]), but not AL (OR = 1.0 [0.9-1.2]). The ORs were higher when at least 2 relatives had a history of cancer or when 1 case occurred before age 46 years. Only HL was significantly associated with a family history of hematopoietic malignancies (OR = 2.0 [1.0-3.8]), mainly because of a significant association with a history of HL (OR = 5.4 [1.3-22]). In conclusion, the study findings support the hypothesis of familial susceptibility to childhood lymphoma, but do not suggest familial susceptibility to childhood AL
Grb2-SH3 ligand inhibits the growth of HER2+ cancer cells and has antitumor effects in human cancer xenografts alone and in combination with docetaxel.

International audienceHER2 represents an important signaling pathway in breast and other cancers. Herceptin has demonstrated clinical activity, but resistance is common. Thus, new therapeutic approaches to the HER2 pathway are needed. Grb2 is an adaptor protein involved in Ras-dependent signaling induced by HER2 receptors. A specific Grb2-SH3 ligand, designed and synthesized in our laboratory, called peptidimer-c, inhibited colony formation in HER2 overexpressing SKBr3 cancer cells. Combined treatment of peptidimer-c with docetaxel further inhibited both colony formation and tumor cell survival compared to docetaxel treatment alone. Efficacy of this combined treatment was correlated with a reduction in the phosphorylation of MAPK and AKT. Finally, peptidimer-c reduced the growth of a HER2(+) human breast cancer (BK111) xenograft in nude mice and potentiated the antitumor effect of docetaxel in a HER2+ hormone-independent human prostate adenocarcinoma (PAC120 HID28) xenograft. These results validate Grb2 as a new target for the HER2 pathway
Role of S128R polymorphism of E-selectin in colon metastasis formation

The extravasation of cancer cells is a key step of the metastatic cascade. Polymorphisms in genes encoding adhesion molecules can facilitate metastasis by increasing the strength of interaction between tumor and endothelial cells as well as impacting other properties of cancer cells. We investigated the Ser128Arg (a561c at the nucleotide level) polymorphism in the E-selectin gene in patients with metastatic colon cancer and its functional significance. Genotyping for a561c polymorphism was performed on 172 cancer patients and on an age-matched control population. The colon cancer group was divided into groups with (M(+)) and without observable metastasis (M(-)). For in vitro functional assays, Huvec transfected cells expressing wild-type (WT) or the S128R variant of E-selectin were established to study in vitro binding ability and signal transduction processes of T84 colon cancer cell line. Our results demonstrated that the Arginine(128) allele was more prevalent in the M(+) group than in the M(-) group or normal controls (p < 0.005; odds ratio, 1.56; 95% confidence interval (CI) 1.16-1.92; p < 0.001, odds ratio = 1.65; CI = 1.24-1.99, respectively). In vitro, S128R E-selectin transfected Huvec cells, supported increased adhesion as well as increased cellular signaling of T84 cancer cells compared to WT E-selectin and mock-transfected Huvec cells. These findings suggest that the E-selectin S128R polymorphism can functionally affect tumor-endothelial interactions as well as motility and signaling properties of neoplastic cells that may modulate the metastatic phenotype
Colorectal cancer screening: A comparison of 35 initiatives in 17 countries

Although in its infancy, organized screening for colorectal cancer (CRC) in the general population is increasing at regional and national levels. Documenting and describing these initiatives is critical to identifying, sharing and promoting best practice in the delivery of CRC screening. Subsequently, the International Colorectal Cancer Screening Network (ICRCSN) was established in 2003 to promote best practice in the delivery of organized screening programs. The initial aim was to identify and document organized screening initiatives that commenced before May 2004. Each identified initiative was sent 1 questionnaire per screening modality: fecal occult blood test, flexible sigmoidoscopy or total colonoscopy. Information was collected on screening methodology, testing details and initiative status. In total, 35 organized initiatives were identified in 17 countries, including 10 routine population-based screening programs, 9 pilots and 16 research projects. Fecal occult blood tests were the most frequently used screening modality, and total colonoscopy was seldom used as a primary screening test. The eligible age for screening ranged from 40 years old to no upper limit; most initiatives included participants aged 50 to 64. Recruitment was usually done by a mailed invitation or during a visit to a family physician. In conclusion, this is the first investigation describing the delivery of CRC screening protocols to various populations. The work of the ICRCSN is enabling valuable information to be shared and a common nomenclature to be established
Reduced expression of IL-18 is a marker of ultraviolet radiation-induced melanomas

We previously showed that mice carrying an activated Cdk4 mutation together with melanocyte-specific mutant Hras (Cdk4R24C/R24C/TPras) develop melanoma spontaneously, but penetrance is increased and age of onset reduced after neonatal UVR exposure. UVR-treated mice were more likely to develop multiple primary lesions, and these melanomas more often expressed Trp53, and less often expressed c-Myc, than melanomas from non-irradiated mice (1). These data suggest differences in mechanisms of tumorigenesis between melanomas developing spontaneously, or as a result of UVR exposure. To further delineate these differences we compared global gene expression between spontaneous and UVR-induced melanomas from these mice using microarrays. We found 264 genes differentially expressed between these groups (ANOVA, p<0.05). Selected candidate genes were validated using qRT-PCR, which confirmed upregulation of Gpr155 and Bmp7, and downregulation of Plagl1, Akap12 and Il18 in UVR-induced mouse melanomas. In humans, epidemiological studies suggest there may be two predominant pathways to melanoma development. One characterized by chronic UVR exposure and which leads mainly to melanomas on sun-exposed sites; the other associated with low UVR exposure and leading predominantly to melanomas on less exposed body sites. We found by immunohistochemical analysis comparing a series of human melanomas from the head (a chronically sun-exposed site; N=82) with a set from the trunk (an intermittently exposed site; N=65), that the prevalence of IL-18 expression was significantly lower in melanomas on the head (16%) than truncal melanomas (34%, p=0.011). We conclude that loss of IL-18 is a marker of UVR-induced melanoma, both in animal models and humans
Low CAIX expression and absence of VHL gene mutation are associated with tumor aggressiveness and poor survival of clear cell renal cell carcinoma.

International audienceWe attempted to describe, in a series of clear cell renal cell carcinoma (RCC), the relationship between CAIX expression, VHL gene mutations, tumor characteristics and outcome. Radical nephrectomy was performed in 100 patients. Genomic DNA was extracted from frozen tumor samples. Four amplimers covering the whole coding sequence of the VHL gene were synthesized by PCR and sequenced. The monoclonal antibody M75 was used to evaluate CAIX protein expression immunohistochemically. VHL mutations were identified in 58 patients (58%) and high CAIX expression (>85%) was observed in 78 (78%). Tumors with VHL mutation showed higher CAIX expression than those without (p = 0.02). Low CAIX expression and absence of VHL mutation were associated with a more advanced tumors e.g., higher T stages and presence of metastases. VHL mutation and high CAIX expression predicted longer progression-free survival (p = 0.037) and disease-specific survival (p = 0.001), respectively. In combination, they defined three prognostic groups (p = 0.002): (i) good prognosis, defined as VHL mutation and high CAIX (2-year survival: 86%), (ii) intermediate prognosis with either VHL mutation or high CAIX (69%), and (iii) poor prognosis with no VHL mutation and low CAIX (45%, median survival 18 months). CAIX expression, but not VHL mutational status, was an independent prognostic factor in multivariate analysis. Taken together, CAIX expression and VHL mutational status are able to stratify patients with clear cell RCC into distinct groups with regards to clinicopathological variables and prognosis, with low CAIX expression and absence of VHL mutation being associated with a poor clinicopathological phenotype and diminished survival
Biophysical and biochemical characterization of a liposarcoma-derived recombinant MnSOD protein acting as an anticancer agent

A recombinant MnSOD (rMnSOD) synthesized by specific cDNA clones derived from a liposarcoma cell line was shown to have the same sequence as the wild-type MnSOD expressed in the human myeloid leukaemia cell line U937, except for the presence of the leader peptide at the N-terminus. These results were fully confirmed by the molecular mass of rMnSOD as evaluated by ES/MS analysis (26662.7 Da) and the nucleotide sequence of the MnSOD cDNA. The role of the leader peptide in rMnSOD was investigated using a fluorescent and/or 68Gallium-labelled synthetic peptide. The labelled peptide permeated MCF-7 cells and uptake could be inhibited in the presence of an excess of oestrogen. In vivo it was taken up by the tumour, suggesting that the molecule can be used for both therapy and diagnosis. The in vitro and in vivo pharmacology tests confirmed that rMnSOD is only oncotoxic for tumour cells expressing oestrogen receptors. Pharmacokinetic studies in animals performed with 125I- and 131I-labelled proteins confirmed  that, when administered systemically, rMnSOD selectively reached the tumour, where its presence was unambiguously demonstrated by scintigraphic and PET scans. PCR analysis revealed that Bax gene expression was increased and the Bcl2 gene was down regulated in MCF7 cells treated with rMnSOD, which suggests that the protein induces a pro-apoptotic mechanism
Patients with Epstein Barr virus-positive lymphomas have decreased CD4(+) T-cell responses to the viral nuclear antigen 1

Epstein Barr virus (EBV) causes lymphomas in immune competent and, at increased frequencies, in immune compromised patients. In the presence of an intact immune system, EBV-associated lymphomas express in most cases only 3 or fewer EBV antigens at the protein level, always including the nuclear antigen 1 of EBV (EBNA1). EBNA1 is a prominent target for EBV-specific CD4(+) T cell and humoral immune responses in healthy EBV carriers. Here we demonstrate that patients with EBV-associated lymphomas, primarily Hodgkin's lymphoma, lack detectable EBNA1-specific CD4(+) T-cell responses and have slightly altered EBNA1-specific antibody titers at diagnosis. In contrast, the majority of EBV-negative lymphoma patients had detectable IFN-gamma expression and proliferation by CD4(+) T cells in response to EBNA1, and carry EBNA1-specific immunoglobulins at levels similar to healthy virus carriers. Other EBV antigens, which were not present in the tumors, were recognized in less EBV positive, than negative lymphoma patients, but detectable responses reached similar CD8(+) T cell frequencies in both cohorts. Patients with EBV-positive and -negative lymphomas did not differ in T-cell responses in influenza-specific CD4(+) T cell proliferation and in antibody titers against tetanus toxoid. These data suggest a selective loss of EBNA1-specific immune control in EBV-associated lymphoma patients, which should be targeted for immunotherapy of these malignancies
Family history of cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.

Alcohol and tobacco consumption are well-recognized risk factors for head and neck cancer (HNC). Evidence suggests that genetic predisposition may also play a role. Only a few epidemiologic studies, however, have considered the relation between HNC risk and family history of HNC and other cancers. We pooled individual-level data across 12 case-control studies including 8,967 HNC cases and 13,627 controls. We obtained pooled odds ratios (OR) using fixed and random effect models and adjusting for potential confounding factors. All statistical tests were two-sided. A family history of HNC in first-degree relatives increased the risk of HNC (OR=1.7, 95% confidence interval, CI, 1.2-2.3). The risk was higher when the affected relative was a sibling (OR=2.2, 95% CI 1.6-3.1) rather than a parent (OR=1.5, 95% CI 1.1-1.8) and for more distal HNC anatomic sites (hypopharynx and larynx). The risk was also higher, or limited to, in subjects exposed to tobacco. The OR rose to 7.2 (95% CI 5.5-9.5) among subjects with family history, who were alcohol and tobacco users. A weak but significant association (OR=1.1, 95% CI 1.0-1.2) emerged for family history of other tobacco-related neoplasms, particularly with laryngeal cancer (OR=1.3, 95% CI 1.1-1.5). No association was observed for family history of nontobacco-related neoplasms and the risk of HNC (OR=1.0, 95% CI 0.9-1.1). Familial factors play a role in the etiology of HNC. In both subjects with and without family history of HNC, avoidance of tobacco and alcohol exposure may be the best way to avoid HNC
Chemotherapy enhances vaccine-induced antitumor immunity in melanoma patients

Combination of chemotherapy with cancer vaccines is currently regarded as a potentially valuable therapeutic approach for the treatment of some metastatic tumors, but optimal modalities remain unknown. We designed a phase I/II pilot study for evaluating the effects of dacarbazine (DTIC) on the immune response in HLA-A2(+) disease-free melanoma patients who received anticancer vaccination 1 day following chemotherapy (800 mg/mq i.v.). The vaccine, consisting of a combination of HLA-A2 restricted melanoma antigen A (Melan-A/MART-1) and gp100 analog peptides (250 microg each, i.d.), was administered in combination or not with DTIC to 2 patient groups. The combined treatment is nontoxic. The comparative immune monitoring demonstrates that patients receiving DTIC 1 day before the vaccination have a significantly improved long-lasting memory CD8(+) T cell response. Of relevance, these CD8(+) T cells recognize and lyse HLA-A2(+)/Melan-A(+) tumor cell lines. Global transcriptional analysis of peripheral blood mononuclear cells (PBMC) revealed a DTIC-induced activation of genes involved in cytokine production, leukocyte activation, immune response and cell motility that can favorably condition tumor antigen-specific CD8(+) T cell responses. This study represents a proof in humans of a chemotherapy-induced enhancement of CD8(+) memory T cell response to cancer vaccines, which opens new opportunities to design novel effective combined therapies improving cancer vaccination effectiveness
Increased frequency of hematopoietic malignancies in relatives of patients with lymphoid neoplasms: a French case-control study.

International audienceLymphoid neoplasms (LNs), including non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), lymphoproliferative syndrome (LPS) and multiple myeloma (MM), are among the most frequent cancers ( approximately 17,000 new cases per year in France), after those related to smoking. LNs were investigated using the data from the ENGELA study. ENGELA is a multicenter hospital-based case-control study that was carried out in France over the period September 2000-December 2004. In all, 822 cases (397 NHL, 149 LH, 168 SLP and 108 MM) and 752 controls were included and described 5,481 and 5,188 first-degree relatives, respectively. A positive association with a familial history of hematopoietic cancer was observed for LN (OR = 1.7 [1.0-2.8]) overall and for LPS (OR = 3.2 [1.4-6.8]). The associations with HL (OR = 10.4 [2.0-53.8]) and NHL (OR = 2.4 [1.0-5.9]) were stronger for men. The associations were also stronger when the disease had been diagnosed before the relatives were aged 45 years. The results mainly support the involvement of genetic factors and suggest that at least some of those factors may be sex-linked. However, the slight overrepresentation of affected spouses among the cases might also support the responsibility of environmental factors
Vitamin D and sun protection : the impact of mixed public health messages in Australia

Exposure of the skin to sunlight can cause skin cancer and is also necessary for cutaneous vitamin D production. Media reports have highlighted the purported health benefits of vitamin D. Our aim was to examine attitudes and behaviours related to sun protection and vitamin D. A cross-sectional study of 2,001 residents in Queensland, Australia aged 20-70 years was undertaken. Information collected included: skin cancer risk factors; perceptions about levels of sun exposure required to maintain vitamin D; belief that sun protection increases risk of vitamin D deficiency; intention, and actual change in sun protection practices for adults and children. Multivariate models examined predictors of attitudinal and behavioural change. One-third (32%) believed a fair-skinned adult, and 31% thought a child required at least 30 minutes per day in summer sun to maintain vitamin D levels. Reductions in sun protection were reported by 21% of adults and 14% of children. Factors associated with belief that sun protection may result in not obtaining enough vitamin D included aged ≥ 60 years (OR=1.35, 95% CI 1.09-1.66) and having skin that tanned easily (OR=1.96, 95% CI 1.38-2.78). Participants from low income households, and those who frequently used sun protective clothing were more likely to have reduced sun protection practices (OR=1.33, 95% CI 1.10-1.73 and OR=1.73, 95% CI 1.36-2.20, respectively). This study provides evidence of reductions in sun protection practices in a population living in a high UV environment. There is an urgent need to re-focus messages regarding sun exposure and for continued sun protection practices
MNS16A minisatellite genotypes in relation to risk of glioma and meningioma and to glioblastoma outcome

The human telomerase reverse transcriptase (hTERT) gene is upregulated in a majority of malignant tumours. A variable tandem repeat, MNS16A, has been reported to be of functional significance for hTERT expression. Published data on the clinical relevance of MNS16A variants in brain tumours have been contradictory. The present population-based study in the Nordic countries and the United Kingdom evaluated brain-tumour risk and survival in relation to MNS16A minisatellite variants in 648 glioma cases, 473 meningioma cases and 1,359 age, sex and geographically matched controls. By PCR-based genotyping all study, subjects with fragments of 240 or 271 by were,judged as having short (S) alleles and subjects with 299 or 331 by fragments as having long (L) alleles. Relative risk of glioma or meningioma was estimated with logistic regression adjusting for age, sex and country. Overall survival,vas analysed using Kaplan-Meier estimates and equality of survival distributions using the log-rank test and Cox proportional hazard ratios. The MNS16A genotype,vas not associated with risk of occurrence of glioma, glioblastoma (GBM) or meningioma. For GBM there were median survivals of 15.3, 11.0 and 10.7 months for the LL, LS and SS genotypes, respectively; the hazard ratio for having the LS genotype compared with the LL was significantly increased HR 2.44 (1.56-3.82) and having the SS genotype versus the LL was nonsignificanlty increased HR 1.46 (0.81-2.61). When comparing the LL versus having one of the potentially functional variants LS and SS, the HR,vas 2.10 (1.41-3.1). However, functionality was not supported as there was no trend towards increasing HR with number of S alleles. Collected data from our and previous studies regarding both risk and survival for the MNS16A genotypes are contradictory and warrant further investigations. (C) 2009 UIC