Thèrése Bocklage

Bio: Thèrése Bocklage is an academic researcher from University of Kentucky. The author has contributed to research in topics: Fine-needle aspiration & Lung cancer. The author has an hindex of 20, co-authored 63 publications receiving 2247 citations. Previous affiliations of Thèrése Bocklage include Mayo Clinic & University of New Mexico.

The XRCC1 399 glutamine allele is a risk factor for adenocarcinoma of the lung.

Abstract: Defects in the repair and maintenance of DNA increase risk for cancer. X-ray cross-complementing group 1 protein (XRCC1) is involved with the repair of DNA single-strand breaks. A nucleotide substitution of guanine to adenine leading to a non-conservative amino acid change was identified in the XRCC1 gene at codon 399 (Arg/Gln). This change is associated with higher levels of aflatoxin B1-adducts and glycophorin A somatic mutations. A case-control study was conducted to test the hypothesis that the 399Gln allele is positively associated with risk for adenocarcinoma of the lung. XRCC1 genotypes were assessed at codon 399 in 172 cases of lung adenocarcinoma and 143 cancer-free controls. Two ethnic populations were represented, non-Hispanic White and Hispanic. The distribution of XRCC1 genotypes differed between cases and controls. Among cases, 47.7% were Arg/Arg, 35.5% were Arg/Gln, and 16.9% were Gln/Gln. Among controls, XRCC1 allele frequencies were 45.5% for Arg/Arg, 44.8% for Arg/Gln, and 9.8% for Gln/Gln. Logistic regression analysis was used to assess the association between lung adenocarcinoma and the G/G genotype relative to the A/A or A/G genotypes. In non-Hispanic White participants, the lung cancer risk associated with the G/G genotype increased significantly after adjustment for age (OR=2.81; 95% CI, 1.2-7.9; P=0.03) and increased further after adjustment for smoking (OR=3.25; 95% CI, 1.2-10.7; P=0.03). Among all groups, a significant association was found between the G/G homozygote and lung cancer (OR=2.45; 95% CI, 1.1-5.8; P=0.03) after adjustment for age, ethnicity, and smoking. This study links a functional polymorphism in the critical repair gene XRCC1 to risk for adenocarcinoma of the lung.

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily

Abstract: We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily.

Promoter Hypermethylation of the O6-Methylguanine-DNA Methyltransferase Gene: More Common in Lung Adenocarcinomas from Never-Smokers than Smokers and Associated with Tumor Progression

Abstract: Adenocarcinoma (AC) is the most common type of lung cancer diag-nosed in the United States, comprising up to 40% of tumors in smokersand 50–80% of tumors in never-smokers. Exposures to cigarette smoke,direct or second-hand, and radiation in the form of radon progeny are themajor risk factors for lung AC in both smokers and never-smokers. Thegoal of the current study was to determine the prevalence for O 6 -methyl-guanine-DNA methyltransferase(MGMT) promoter methylation in a largesample of central or peripheral ACs from smokers (n 157), formeruranium miners (n cating that differences in lipid solubility can affect the distribution of34), and never-smokers (n 46). The mutation rateat codon 12 of the K-rasgene was determined to assess whether activationof this oncogene was associated with MGMT methylation. The overallprevalence for MGMT methylation was 51%. Significantly more tumorsfrom never-smokers than smokers exhibitedMGMT methylation (66 ver-sus 47%, respectively). In contrast, exposure to radon through uraniummining did not affect the prevalence for methylation. The frequency ofMGMT methylation was increased significantly in association with tumorstage. K-rasmutations were detected in 24% of all ACs and 22, 24, and28% of tumors from never-smokers, smokers, and miners, respectively.Alterations in both the K-rasand MGMT genes were seen in only 11% ofACs. Kaplan-Meier survival estimates did not reveal any difference be-tween patient survival with or without MGMT methylation. In contrast,survival was significantly reduced over the initial 60 months after diag-nosis for patients with a transition mutation in the K-rasgene comparedwith those with a transversion mutation. This investigation demonstratesthat MGMT promoter hypermethylation is a common event in the pro-gression of early stage AC of the lung. We have shown that the incidenceof MGMT methylation was significantly higher in never-smokers thansmokers and have detected a higher frequency of mutations within theK-rasgene than previously reported in never-smokers. This study alsosuggests that K-ras activation is independent ofMGMT methylation.

Predicting gene promoter methylation in non-small-cell lung cancer by evaluating sputum and serum.

Abstract: The use of 5-methylcytosine demethylating agents in conjunction with inhibitors of histone deacetylation may offer a new therapeutic strategy for lung cancer. Monitoring the efficacy of gene demethylating treatment directly within the tumour may be difficult due to tumour location. This study determined the positive and negative predictive values of sputum and serum for detecting gene methylation in primary lung cancer. A panel of eight genes was evaluated by comparing methylation detected in the primary tumour biopsy to serum and sputum obtained from 72 patients with Stage III lung cancer. The prevalence for methylation of the eight genes in sputum (21-43%) approximated to that seen in tumours, but was 0.7-4.3-fold greater than detected in serum. Sputum was superior to serum in classifying the methylation status of genes in the tumour biopsy. The positive predictive value of the top four genes (p16, DAPK, PAX5 beta, and GATA5) was 44-72% with a negative predictive value for these genes > or =70%. The highest specificity was seen for the p16 gene, and this was associated with a odds ratio of six for methylation in the tumour when this gene was methylated in sputum. In contrast, for serum, the individual sensitivity for all genes was 6-27%. Evaluating the combined effect of methylation of at least one of the four most significant genes in sputum increased the positive predictive value to 86%. These studies demonstrate that sputum can be used effectively as a surrogate for tumour tissue to predict the methylation status of advanced lung cancer where biopsy is not feasible.

Genome maintenance mechanisms for preventing cancer

Abstract: The early notion that cancer is caused by mutations in genes critical for the control of cell growth implied that genome stability is important for preventing oncogenesis. During the past decade, knowledge about the mechanisms by which genes erode and the molecular machinery designed to counteract this time-dependent genetic degeneration has increased markedly. At the same time, it has become apparent that inherited or acquired deficiencies in genome maintenance systems contribute significantly to the onset of cancer. This review summarizes the main DNA caretaking systems and their impact on genome stability and carcinogenesis.

Molecular origins of cancer: Lung cancer

Abstract: From the Departments of Thoracic/Head and Neck Medical Oncology (R.S.H., J.V.H., S.M.L.), Cancer Biology (R.S.H., J.V.H.), and Clinical Cancer Prevention (S.M.L.), University of Texas M.D. Anderson Cancer Center, Houston. Address reprint requests to Dr. Lippman at the Department of Thoracic/Head and Neck Medical Oncology, Unit 432, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, or at slippman@ mdanderson.org.

Pathology and genetics of tumours of the lung , pleura, thymus and heart

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Biomedical Applications of Biodegradable Polymers

Abstract: Utilization of polymers as biomaterials has greatly impacted the advancement of modern medicine. Specifically, polymeric biomaterials that are biodegradable provide the significant advantage of being able to be broken down and removed after they have served their function. Applications are wide ranging with degradable polymers being used clinically as surgical sutures and implants. In order to fit functional demand, materials with desired physical, chemical, biological, biomechanical and degradation properties must be selected. Fortunately, a wide range of natural and synthetic degradable polymers has been investigated for biomedical applications with novel materials constantly being developed to meet new challenges. This review summarizes the most recent advances in the field over the past 4 years, specifically highlighting new and interesting discoveries in tissue engineering and drug delivery applications.