Liquid Flyback Booster Pre-Phase A Study Assessment

Mw concept of a flyback booster has been around since early in the Shuttle program. The original two-stage Shuttle concepts used a manned flyback booster. These boosters were eliminated from the program for funding and size reasons. The current Shuttle uses two Redesigned Solid Rocket Motors (RSRMs), which are recovered and refurbished after each flight; this is one of the major cost factors of the program. Replacement options have been studied over the past ten years. The conclusion reached by the most recent study is that the liquid flyback booster (LFBB) is the only competitive option from a life-cycle cost perspective. The purpose of this study was to assess the feasibility and practicality of LFBBs. The study provides an expansion of the recommendations made during the during the aforementioned study. The primary benefits are the potential for enhanced reusability and a reuction of recurring costs. The potential savings in vehicle turnaround could offset the up-front costs. Development of LFBBs requires a commitment to the Shuttle program for 20 to 30 years. LFBBs also offer enhanced safety and abort capabilities. Currently, any failure of an RSRM can be considered catastrophic since them we no intact abort capabilities during the burn of the RSRMS. The performance goal of the LFBBs was to lift a fully loaded Orbiter under optimal conditions, so as not to be the limiting factor of the performance capability of the Shuttle. In addition, a final benefit is the availability of growth paths for applications other than the Shuttle

K-ras mutations in the duodenal fluid of patients with pancreatic carcinoma

Many patients with carcinoma of the pancreas die because their disease is not detected until late in its course. Methods that detect these cancers earlier will improve patient outcome. Over 80% of pancreatic carcinomas contain mutations in codon 12 of the K-ras gene. Screening duodenal fluid for these mutations may lead to early detection of these cancers and assist in establishing a diagnosis of pancreatic carcinoma. Polymerase chain reaction (PCR), with and without restriction enzyme-mediated mutant enrichment, was performed on DNA isolated from duodenal fluid specimens from 61 patients who underwent pancreaticoduodenectomy (Whipple's operation) for either periampullary cancer or a benign condition of the pancreas. Representative sections of pancreas pathology (primary carcinoma, benign tumor, or chronic pancreatitis) from the patients with duodenal fluid specimens containing amplifiable DNA were also analyzed for K-ras mutations. Wild-type and mutant K-ras were detected by hybridization of the PCR products with K-ras codon 12 mutant and wild-type specific probes. Seven of the 61 duodenal fluid specimens contained DNA that did not amplify. Thirteen (24% of the 54 duodenal fluid specimens with amplifiable DNA and 21% of the total of 61 specimens) contained activating point mutations at codon 12 of the K-ras gene. Mutations were detected in 13 of the 51 duodenal fluid specimens from patients with cancer (sensitivity, 25%), whereas mutations were not detected in any of the 9 amplifiable duodenal fluid specimens from patients with benign conditions of the pancreas (specificity, 100%). One duodenal fluid specimen from a patient with adenocarcinoma of the pancreas had two different K-ras mutations. DNA from three of the primary carcinomas did not amplify or was not available. Twenty-nine (69%) of the 42 primary tumors with amplifiable DNA contained K-ras mutations, whereas 3 (30%) of the 10 pancreata with benign conditions harbored mutations. Twenty-two (65%) of 34 ductal adenocarcinomas of the pancreas with amplifiable DNA had K-ras mutations. It is noteworthy that the same mutation was present in both the duodenal fluid and the primary carcinomas of 11 (92%) of the 12 patients who had primary tumors with amplifiable DNA as well as K-ras mutations in their duodenal fluid specimens. The identification of genetic alterations in cancer-causing genes in duodenal fluid may form the basis for the development of new approaches to the detection of carcinoma of the pancreas. Some pancreata without cancer, however, may also harbor K-ras mutations, potentially limiting the specificity of K-ras-based test

Early-onset gastric cancers have a different molecular expression profile than conventional gastric cancers

Many studies examine the molecular genetics of gastric cancer, but few look at young patients in particular and there is no comparison of molecular expression between early-onset gastric cancer ( <or = 45 years old) and conventional gastric cancers. Expression of cycloxygenase-2 (COX-2) is elevated in gastric adenocarcinomas compared to non-neoplastic mucosa, and in light of studies showing reduced risk of gastric cancer in nonsteroidal anti-inflammatory drug users, we have chosen to investigate the expression of COX-2 and related molecules in 113 early-onset gastric cancers and compare it with 91 conventional gastric cancers, using tissue microarrays. These markers include molecules known to be important in conventional gastric carcinogenesis, such as E-Cadherin, p53, COX-2, Trefoil Factor-1 (TFF1), beta-catenin, p16 and c-myc; as well as molecules not yet described as being important in gastric cancer, such as the transcription factor c-jun, the COX-2 mRNA stabilizer HuR, and C/EBP-beta, a transcription factor for COX-2. All markers showed a statistically significant difference between early-onset gastric cancers and conventional gastric cancers, using a chi2 test. In particular, early-onset gastric cancers displayed a COX-2 Low, TFF1-expressing phenotype, whereas COX-2 overexpression and loss of TFF1 was found in conventional cancers, and this difference between early-onset gastric cancers and conventional cancers remained statistically significant when adjusted for location and histology (P <0.0001 and P = 0.002 respectively). We found that COX-2 overexpression correlates significantly with loss of TFF1 (P = 0.001), overexpression of C/EBP-beta (P <0.001) and cytoplasmic HuR (P = 0.016). COX-2 was significantly associated with p53 positivity (P = 0.003). Abnormalities in E-Cadherin correlated significantly with diffuse phenotype, whereas high expression of COX-2, loss of TFF1 and overexpression of C/EBP-beta correlated with the intestinal phenotype. Our results provide further evidence that early-onset gastric cancer exhibits a distinctive expression profile that may have practical implication

Can K-ras codon 12 mutations be used to distinguish benign bile duct proliferations from metastases in the liver? A molecular analysis of 101 liver lesions from 93 patients.

It can be difficult to distinguish benign bile duct proliferations (BDPs) from well-differentiated metastatic peripancreatic adenocarcinomas on histological grounds alone. Most peripancreatic carcinomas harbor activating point mutations in codon 12 of the K-ras oncogene, suggesting that K-ras mutational status may provide a molecular basis for distinguishing BDPs from liver metastases. The ability of tests for mutations in codon 12 of K-ras to make this distinction was examined in a two-part study. In the first part we determined the K-ras mutational status of 56 liver lesions and 48 primary peripancreatic adenocarcinomas obtained from 48 patients. In the second part of this study an additional 45 liver lesions were studied. In the first 48 patients, activating point mutations in codon 12 of K-ras were detected in 28 (61%) of the 46 primary carcinomas, in 8 (100%) of 8 liver metastases, in 2 (6.5%) of 31 BDPs, and in none (0%) of 14 liver granulomas. Three BDPs and two primary carcinomas did not amplify. To further estimate the prevalence of K-ras mutations in BDPs we analyzed an additional series of 45 mostly incidental BDPs for K-ras mutations. Three (6.7%) of these 45 harbored K-ras mutations. These results suggest that K-ras mutations may be useful in distinguishing BDPs from metastases in the liver; however, there is some overlap in the mutational spectra of BDPs and pancreatic carcinomas

Cyclin E low molecular weight isoforms occur commonly in early-onset gastric cancer and independently predict survival

BACKGROUND: Post-translational cleavage of full-length cyclin E from the N-terminus can produce low molecular weight (LMW) isoforms of cyclin E containing the C-terminus only. AIM: To assess their presence in early-onset gastric cancer (EOGC), stump cancers and conventional gastric cancers and ascertain how they influence survival in EOGC. METHODS: The expression of full-length and LMW isoforms of cyclin E in 330 gastric cancers, including early-onset gastric cancer (EOGC), stump cancer and conventional gastric cancer (>45 years old) was compared using antibodies targeted to the N- and C-terminals. RESULTS: LMW isoforms were found in 35% of EOGCs, compared to 8% of conventional gastric cancers and 4% of stump cancers; their presence was visualised in cell lines using western blot analysis. In addition, C-terminal staining was a positive predictor of survival in EOGC. In contrast, no correlation with survival was found with the N-terminal antibody which detects only full-length cyclin E. CONCLUSION: EOGCs have a unique molecular phenotype and LMW isoforms of cyclin E may independently influence survival in EOG

Genetic defects underlying Peutz-Jeghers syndrome (PJS) and exclusion of the polarity-associated MARK/Par1 gene family as potential PJS candidates

LKB1/STK11 germline inactivations are identified in the majority (66–94%) of Peutz–Jeghers syndrome (PJS) patients. Therefore, defects inother genes or so far unidentified ways of LKB1 inactivation may cause PJS. The genes encoding the MARK proteins, homologues of the Par1 polarity protein that associates with Par4/Lkb1, were analyzed in this study because of their link to LKB1 and cell polarity. The genetic defect underlying PJS was determined through analysis of both LKB1 and all four MARK genes. LKB1 point mutations and small deletions were identified in 18 of 23 PJS families using direct sequencing and multiplex ligation-dependent probe amplification analysis identified exon deletions in 3 of 23 families. In total, 91% of the studied families showed LKB1 inactivation. Furthermore, a MARK1, MARK2, MARK3 and MARK4 mutation analysis and an MARK4 quantitative multiplex polymerase chain reaction analysis to identify exon deletions on another eight PJS families without identified LKB1 germline mutation did not identify mutations in the MARK genes. LKB1 defects are the major cause of PJS and genes of the MARK family do not represent alternative PJS genes. Other mechanisms of inactivation of LKB1 may cause PJS in the remaining families

Genetic defects underlying Peutz-Jeghers syndrome (PJS) and exclusion of the polarity-associated MARK/Par1 gene family as potential PJS candidates

LKB1/STK11 germline inactivations are identified in the majority (66-94%) of Peutz-Jeghers syndrome (PJS) patients. Therefore, defects in other genes or so far unidentified ways of LKB1 inactivation may cause PJS. The genes encoding the MARK proteins, homologues of the Par1 polarity protein that associates with Par4/Lkb1, were analyzed in this study because of their link to LKB1 and cell polarity. The genetic defect underlying PJS was determined through analysis of both LKB1 and all four MARK genes. LKB1 point mutations and small deletions were identified in 18 of 23 PJS families using direct sequencing and multiplex ligation-dependent probe amplification analysis identified exon deletions in 3 of 23 families. In total, 91% of the studied families showed LKB1 inactivation. Furthermore, a MARK1, MARK2, MARK3 and MARK4 mutation analysis and an MARK4 quantitative multiplex polymerase chain reaction analysis to identify exon deletions on another eight PJS families without identified LKB1 germline mutation did not identify mutations in the MARK genes. LKB1 defects are the major cause of PJS and genes of the MARK family do not represent alternative PJS genes. Other mechanisms of inactivation of LKB1 may cause PJS in the remaining familie