Development of colorectal cancer gene therapy

Colorectal cancer is the number two cancer killer in the United States. Although primary colorectal cancer can be resected by surgery, patients often die from metastatic disease. Liver is the most common site of metastasis for colorectal cancer. It is difficult to selectively kill metastatic colon cancer cells without damaging normal liver functions. Thus it becomes a high priority to develop a selective targeting system for the treatment of colorectal cancer liver metastasis. ^ In the current study, a gene therapy strategy that allows a therapeutic gene to selectively destroy metastatic colon cancer cells without affecting normal liver cells is developed. The APC gene is frequently mutated in colorectal cancers. These mutations activate β-catenin responsive promoters. An optimized β-catenin responsive promoter, containing TCF consensus binding sites, was engineered for this study. This TCF promoter was found to express preferentially in APC mutated/β-catenin activated colorectal cancers while maintaining a low expression level in cell lines of liver origin. A recombinant adenoviral vector AdTCF-TK, in which the TCF promoter controls expression of the herpes simplex virus thymidine kinase gene, selectively destroyed colorectal cancer cells in vitro. AdTCF-TK virus and ganciclovir treatment also inhibited the growth of solid tumour derived from the colon cancer cell line DLD-1 in nude mice. In a control experiment, the growth inhibition effect of the same virus was attenuated in a liver cancer cell line. ^ In the present study, a novel method was developed to target therapeutic gene expression to colon cancer cells at reduced liver toxicity to the patients. The same gene therapy design may also be applied to treat tumours carrying mutations in the β-catenin gene, which is a central component of the APC signal transduction pathway. In summary, the principle for a rational design of a cancer specific treatment approach is demonstrated in this study. In the future, mutations in cancer patients will be more easily identified. Using the same principle developed in this study, specific regimen can be designed to treat these patients based on the specific genetic changes found in the tumour. ^

The association of HSV 1 and 2 with atherosclerosis defined by CRP level

A study of the association of Herpes simplex virus 1 and 2 exposure to early atherosclerosis using high C-reactive protein level as a marker was carried out in US born, non-pregnant, 20-49 year olds participating in a national survey between 1999 and 2004. Participants were required to have valid results for Herpes simplex virus 1 and 2 and C-Reactive Protein for inclusion. Cases were those found to have a high C-reactive protein level of 0.3-1 mg/dL, while controls had low to normal values (0.01-0.29 mg/dL). Overall, there were 1211 cases and 2870 controls. Mexican American and non-Hispanic black women were much more likely to fall into the high cardiac risk group than the other sex race groups with proportions of 44% and 39%, respectively. ^ Herpesvirus exposure was categorized such that Herpes simplex virus 1 and 2 exposure could be studied simultaneously within the same individual and models. The HSV 1+, HSV 2- category included the highest percentage (45.63%) of participants, followed by HSV 1-, HSV 2- (30.16%); HSV 1+, HSV 2+ (15.09%); and HSV 1-, HSV 2+ (9.12%) respectively. The proportion of participants in the HSV 1+, HSV 2- category was substantially higher in Mexican Americans (63%-66%). Further, the proportion in the HSV 1+, HSV 2+ category was notably higher in the non-Hispanic black participants (23%-44%). Non-Hispanic black women also had the highest percentage of HSV 1-, HSV 2+ exposure of all the sex race groups at 17%. ^ Overall, the unadjusted odds ratios for atherosclerotic disease defined by C-reactive protein with HSV 1-, HSV 2- as the referent group was 1.62 (95% CI 1.23-2.14) for HSV 1 +, HSV 2+; 1.3 (95% CI 1.10-1.69 for HSV 1+, HSV 2-; and 1.52 (95% CI 1.14-2.01). When the study was stratified into sex-race groups, only HSV 1+, HSV 2- in the Non-Hispanic white men remained significant (OR=1.6; 95% CI 1.06-2.43). Adjustment for selected covariates was made in the multivariate model for both the overall and sex-race stratified studies. High C-reactive protein values were not associated with any of the Herpesvirus exposure levels in either the overall or stratified analyses. ^

An ordinal logistic regression model with misclassification of the outcome variable and categorical covariate

Ordinal outcomes are frequently employed in diagnosis and clinical trials. Clinical trials of Alzheimer's disease (AD) treatments are a case in point using the status of mild, moderate or severe disease as outcome measures. As in many other outcome oriented studies, the disease status may be misclassified. This study estimates the extent of misclassification in an ordinal outcome such as disease status. Also, this study estimates the extent of misclassification of a predictor variable such as genotype status. An ordinal logistic regression model is commonly used to model the relationship between disease status, the effect of treatment, and other predictive factors. A simulation study was done. First, data based on a set of hypothetical parameters and hypothetical rates of misclassification was created. Next, the maximum likelihood method was employed to generate likelihood equations accounting for misclassification. The Nelder-Mead Simplex method was used to solve for the misclassification and model parameters. Finally, this method was applied to an AD dataset to detect the amount of misclassification present. The estimates of the ordinal regression model parameters were close to the hypothetical parameters. β1 was hypothesized at 0.50 and the mean estimate was 0.488, β2 was hypothesized at 0.04 and the mean of the estimates was 0.04. Although the estimates for the rates of misclassification of X1 were not as close as β1 and β2, they validate this method. X 1 0-1 misclassification was hypothesized as 2.98% and the mean of the simulated estimates was 1.54% and, in the best case, the misclassification of k from high to medium was hypothesized at 4.87% and had a sample mean of 3.62%. In the AD dataset, the estimate for the odds ratio of X 1 of having both copies of the APOE 4 allele changed from an estimate of 1.377 to an estimate 1.418, demonstrating that the estimates of the odds ratio changed when the analysis includes adjustment for misclassification. ^

Mandating the HPV vaccine

Background. HPV is the underlying cause of cervical cancer, a malignant tumor of the female genital tract. Each year, cervical cancer is newly diagnosed in approximately 10,000 women, and over 3,000 women die from the malignancy. In addition, HPV is implicated as a cause of other cancers involving the genital tract, male and female, and the head and neck. ^ Gardasil, a vaccine against HPV, was licensed by the FDA in June 2006. Early study results have shown Gardasil to be safe and effective at preventing HPV infections that are commonly associated with the development of cervical cancer, as well as other HPV-related cancers and genital warts. The vaccine is most effective when administered in childhood, before initial exposure to HPV, which typically occurs shortly after the onset of sexual activity. Accordingly, the CDC's Advisory Committee on Immunization Practices (ACIP) has recommended routine vaccination of females aged 11-12 years. ^ Taking the ACIP recommendation one step further, many states have considered school-based mandates of the HPV vaccine in an attempt to reduce the burden of HPV-related illness, in particular to reduce the disparately high incidence of cervical cancer in medically underserved populations. These mandate attempts have sparked heated debate—highlighting public concerns regarding adolescent sexuality, corporate greed, and vaccines in general. ^ Methods. My research focuses on publicly available sources of information such as medical journals, government reports (federal and state), NGO reports, newspapers, and books. I begin with a background discussion of HPV, cervical cancer, and the HPV vaccine. I then discuss public health policy issues related to vaccines, vaccine mandates, and HPV-related illness. Specifically, I discuss the public health benefit of previous vaccine mandates, the legality of vaccine mandates, and the undue corporate influence on the politics of instituting HPV vaccine mandates. In addition, I examine some of the causes behind the anti-vaccine movement and the controversy surrounding adolescent sexuality as it pertains to the HPV vaccine. In the final section, I focus on the recent failed attempt by Governor Rick Perry to mandate the HPV vaccine in Texas. A retrospective analysis of Governor Perry's policy decisions is undertaken and recommendations are made regarding future attempts to mandate the HPV vaccine, or other vaccines under development for similar sexually transmitted viral diseases such as HIV and herpes simplex. ^ Results. In Texas, as in other states across the country, HPV vaccine mandates faced opposition from those who, while they may support mandates of other vaccines, oppose mandates for the HPV vaccine based largely on the idea that HPV is a sexually transmitted disease—they see responsible sexual behavior as the appropriate method for preventing HPV-related illness. A second major group of opposition comes from those who are generally opposed to all vaccine mandates, due to concerns that mandates are intended primarily for the financial benefit of the pharmaceutical industry or due to concerns—largely unfounded—that vaccines pose a greater health threat than the illnesses they are designed to prevent. ^ Conclusion. In order to reduce opposition to vaccine mandates, care must be taken to educate the public regarding the benefits of vaccination by mobilizing the public health sector, avoid the impression that the decision to institute mandates is rash or pressured by allowing time for open debate, and minimize lobbying efforts by vaccine manufacturers. ^

Late Pliocene and Early Pleistocene dinoflagellate cysts and sea surface temperture reconstruction for several IODP and DSDP sites in the North Atlantic

In an attempt to document the palaeoecological affinities of individual extant and extinct dinoflagellate cysts, Late Pliocene and Early Pleistocene dinoflagellate cyst assemblages have been compared with geochemical data from the same samples. Mg/Ca ratios of Globigerina bulloides were measured to estimate the spring-summer sea-surface temperatures from four North Atlantic IODP/DSDP sites. Currently, our Pliocene-Pleistocene database contains 204 dinoflagellate cyst samples calibrated to geochemical data. This palaeo-database is compared with modern North Atlantic and global datasets. The focus lies in the quantitative relationship between Mg/Ca-based (i.e. spring-summer) sea-surface temperature (SSTMg/Ca) and dinoflagellate cyst distributions. In general, extant species are shown to have comparable spring-summer SST ranges in the past and today, demonstrating that our new approach is valid for inferring spring-summer SST ranges for extinct species. For example, Habibacysta tectata represents SSTMg/Ca values between 10° and 15°C when it exceeds 30% of the assemblage, and Invertocysta lacrymosa exceeds 15% when SSTMg/Ca values are between 18.6° and 23.5°C. However, comparing Pliocene and Pleistocene SSTMg/Ca values with present day summer values for the extant Impagidinium pallidum suggests a greater tolerance of higher temperatures in the past. This species occupies more than 5% of the assemblage at SSTMg/Ca values of 11.6-17.9°C in the Pliocene and Pleistocene, whereas present day summer SSTs are around -1.7 to 6.9°C. This observation questions the value of Impagidinium pallidum as reliable indicator of cold waters in older deposits, and may explain its bipolar distribution.

Pollen and macroremains from sediment core Aschenhütte

The Upper Pleistocene sediments of the Aschenhütte sink-hole (west of Herzberg am Harz, Lower Saxony) enable one to make interesting correlations between palynological and geological results. The sequence is composed of limnic-telmatic deposits (Eemain to Lower Weichselian) and loess with paleosoils (Weichselian). Sedimentation started during the hornbeam-dominated phase of the Eemian interglacial period and continued throughout the Eemian, the Weichselian Brörup interstadial (sensu Andersen) and parts of the preceding and the following stadial phases, the Herning and the Rederstall stadials. As opposed to most of the known Eemian sites spruce was a major tree species during the hornbeam-dominated phase of the Eemian. The vegetational development during the interstadial phase does not show a period of climatic deterioration as is the case for the Brörup interstadial when considering regions with a more demanding vegetation or regions close to the natural boundaries of the tree species concerned. Pollen or seeds of Bruckenthalia and Picea omoricoides have not been found in the Aschenhütte cores. The limnic-telmatic sediments interlock with loess-paleosoils (Eemian soil and Lower Weichselian bleaching soils) at the lake shore. They are overlaid by loess paleosoils of the Stillfried-B interstadial (Hattorf soil and Lohne soil). Lake level fluctuations were determined by means of the facies distribution and isochrones as defined by pollen analysis. A relatively high stand of the lake level existed after the end of the Eemian interglacial and during the Brörup interstadial periods. In the course of the Herning stadial period the water level dropped, whereas during the Rederstall stadial phase the lake basin was covered by sediments and therefore dried up.

Foraminifera and microfossil occurence in Late Jurassic sediments of the North and South Atlantic

Biostratigraphical, taxonomical, and palaeocological results were obtained from Oxfordian to Tithonian foraminifers of the Northern and Southern Atlantic Ocean boreholes of the DSDP Legs 1, 11, 36, 41, 44, 50, and 79. An oversight on the cored Jurassic sections of the DSDP Legs 79 and the corresponding foraminiferal descriptions are given. The reddish brown, clayey and carbonaceous Cat Gap Formation (Oxfordian to Tithonian) of the Northern Atlantic Ocean, rich in radiolarians, yields less or more uniform, in most cases allochthonous foraminiferal faunas of Central European shelf character. No Callovian and Upper Tithonian foraminiferaI zones can be established. The zone of Pseudomarssonella durnortieri covers the Oxfordian/Kimmeridgian, the zone of Neobulimina atlantica the Kimmeridgian/Lower Tithonian interval. Characteristic foraminiferal faunas are missing since the Upper Tithonian to Valanginian for reason of a widely distributed regression which caused hiatuses observed all over the Northern Atlantic Ocean and in parts of Europe. The Upper Jurassic cannot be subdivided into single stages by foraminiferal biostratigraphy alone. The fovaminiferal zones established by Moullad (1984) covering a Callovian-Tithonian interval may be of some local importance in the Tethyan realm: It has too long-ranging foraminiferal species to be used as index marker in the word-wide DSDP boreholes. Some taxonomical confusion is caused because in former publications some foraminiferal species have got different names both in the Jurassic and Cretaceous. The foraminiferal biostratigraphy of drilled sections from DSDP boreholes is restricted by the drilling technique and for palaeo-oceanographical, biological, and geological reasons. Foraminiferal faunas from the DSDP originally described as ,,bathyal, or ,,abyssal,, have to be derived from shallower water. This contrasts the palaeo-water depths of 3000-4000 m which result from sedimentological and palaeo-geographical investigations.

Mid-Cretaceous planktonic foraminifera off central Morocco

Sites 545 and 547 collectively penetrated 629 m of mid-Cretaceous strata (upper Aptian to upper Cenomanian) off central Morocco during Leg 79 of the Deep Sea Drilling Project. Site 545, at the base of the steep Mazagan Escarpment, records a virtually complete succession of hemipelagic sediments of early late Aptian to middle Cenomanian age. Minor faunal recycling occurred throughout much of the upper Aptian to middle Albian part of the sequence (Cores 55 through 41), reflecting bottom currents along the Mazagan Escarpment. This may be related to the strong upwelling regime and high surface water productivity over Site 545 during the latest Aptian through middle Albian. The upwelling system ceased rather abruptly in this area in late middle Albian time. Recycling of older strata by bottom currents also ceased in the late middle Albian and resulted in a slower average accumulation rate in the upper Albian to middle Cenomanian section of Site 545 (Cores 40 through 28). However, intervals of pebbly claystone conglomerates in Cores 40 and 34 record sporadic instability in the slope adjacent to Site 545. Site 547, located only about 15 km seaward, is situated in a small sub-basin adjacent to the basement block drilled by Site 544. It contains an expanded upper Albian to upper Cenomanian sequence as a result of the numerous conglomeratic intervals throughout much of the section. In contrast to Site 545, the conglomerates were not derived from older strata cropping out on the Mazagan Escarpment; rather, they originated penecontemporaneously from a local unstable slope. A detailed biostratigraphic framework based on planktonic foraminifers is established for the mid-Cretaceous sections of Sites 545 and 547 and a new composite zonal scheme is proposed for the early late Aptian through early late Cenomanian interval. Fifty-five species are recognized and illustrated

Lower Cretaceous planktonic foraminifer stratigraphy of sediments from ODP Leg 171B sites

During Ocean Drilling Program Leg 171B, an Aptian to Turonian sedimentary succession yielding exceptionally well-preserved planktonic foraminiferal faunas was recovered at Sites 1049, 1050, and 1052. Most of the standard Tethyan planktonic foraminiferal zones have been recognized within the mid-Cretaceous section, with the exception of two Albian zones not reached by any of the drilled holes. In addition, some emphasis is brought here on the current problems concerning the definition of the Aptian/Albian and Albian/Cenomanian boundaries.