DNA nucleotide excision repair gene single nucleotide polymorphisms and hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease caused by germline mutations in DNA mismatch repair(MMR) genes. The nucleotide excision repair(NER) pathway plays a very important role in cancer development. We systematically studied interactions between NER and MMR genes to identify NER gene single nucleotide polymorphism (SNP) risk factors that modify the effect of MMR mutations on risk for cancer in HNPCC. We analyzed data from polymorphisms in 10 NER genes that had been genotyped in HNPCC patients that carry MSH2 and MLH1 gene mutations. The influence of the NER gene SNPs on time to onset of colorectal cancer (CRC) was assessed using survival analysis and a semiparametric proportional hazard model. We found the median age of onset for CRC among MMR mutation carriers with the ERCC1 mutation was 3.9 years earlier than patients with wildtype ERCC1(median 47.7 vs 51.6, log-rank test p=0.035). The influence of Rad23B A249V SNP on age of onset of HNPCC is age dependent (likelihood ratio test p=0.0056). Interestingly, using the likelihood ratio test, we also found evidence of genetic interactions between the MMR gene mutations and SNPs in ERCC1 gene(C8092A) and XPG/ERCC5 gene(D1104H) with p-values of 0.004 and 0.042, respectively. An assessment using tree structured survival analysis (TSSA) showed distinct gene interactions in MLH1 mutation carriers and MSH2 mutation carriers. ERCC1 SNP genotypes greatly modified the age onset of HNPCC in MSH2 mutation carriers, while no effect was detected in MLH1 mutation carriers. Given the NER genes in this study play different roles in NER pathway, they may have distinct influences on the development of HNPCC. The findings of this study are very important for elucidation of the molecular mechanism of colon cancer development and for understanding why some mutation carriers of the MSH2 and MLH1 gene develop CRC early and others never develop CRC. Overall, the findings also have important implications for the development of early detection strategies and prevention as well as understanding the mechanism of colorectal carcinogenesis in HNPCC. ^

Carcinoma of the lower uterine segment: A newly described association with Lynch Syndrome

Purpose. We performed a case-comparison study to describe the characteristics of LUS tumors and their association with risk factors for endometrial cancer. ^ Patients and Methods. From January 1996 through October 2007, 3,892 women were identified with a diagnosis of primary endometrial carcinoma or primary cervical adenocarcinoma. Pathology records from the 1,009 women who had a hysterectomy were reviewed. Subjects were included in the LUS group only if the tumor was clearly originating from the area between the lower corpus and upper cervix in the hysterectomy specimen. The LUS group was compared to all patients with endometrial corpus carcinoma who underwent hysterectomy at our institution in a 12-month period randomly selected from the study period. Risk factors for endometrial carcinoma such as body mass index (BMI) and Lynch Syndrome were assessed. Expression of estrogen receptor (ER), vimentin, carcinoembryonic antigen (CEA), p16, and human papilloma virus DNA (HPV DNA) was assessed; this panel is known to be effective in distinguishing adenocarcinomas of endometrial versus endocervical origin. Fisher's Exact, Chi-square, Mann-Whitney, and Student's t-tests were utilized for statistical analysis. ^ Results. Thirty-five of 1,009 women had endometrial carcinoma of the LUS (3.5%; 95% CI: 2–4%). Compared to patients with corpus tumors, LUS patients were younger (54.2 vs. 62.9 years, P = .001), had higher stage (P < .001), and more invasive tumors (P = .001). Preoperative diagnosis of the LUS tumors more frequently included the possibility of endocervical adenocarcinoma ( P < .001), leading to preoperative radiation therapy in 4 patients. Median BMI was similar in the LUS and corpus groups. Seventy-three percent of the available LUS tumors had a similar immunohistochemical expression pattern to conventional endometrioid adenocarcinoma. Because of the young median age for the LUS group, we performed immunohistochemistry for Lynch syndrome-associated DNA mismatch repair proteins MLH1, MSH2, MSH6, and PMS2. Microsatellite instability testing (MSI) and MLH1 promoter hypermethylation were performed when indicated. Thirty-six percent of the LUS tumors were MSI-high. Ten of thirty-five (29%) women with LUS tumors were either confirmed to have Lynch Syndrome or were strongly suspected to have Lynch Syndrome based on tissue-based molecular assays (95% CI, 16 to 45%). ^ Conclusions. Endometrial carcinoma arising in the LUS is a clinical and pathologic entity which can be diagnostically confused with cervical adenocarcinoma. In general, LUS tumors can be correctly identified as being endometrial carcinoma using the immunohistochemical panel noted above. The prevalence of Lynch Syndrome in patients with LUS tumors is much greater than that of the general endometrial cancer population (1.8%) or in endometrial cancer patients younger than 50 years of age (8–9%). Based on our results, the possibility of Lynch Syndrome should be considered in women with LUS tumors. ^

THE EFFECT OF PERSON-ENVIRONMENT INTERACTION ON ANXIETY, DEPRESSION, AND SUBJECTIVE DISTRESS OF OPTOMETRY STUDENTS

The purpose of this study was to investigate whether an incongruence between personality characteristics of individuals and concomitant charcteristics of health professional training environments on salient dimensions contributes to aspects of mental health. The dimensions examined were practical-theoretical orientation and the degree of structure-unstructure. They were selected for study as they are particularly important attributes of students and of learning environments. It was proposed that when the demand of the environment is disparate from the proclivities of the individual, strain arises. This strain was hypothesized to contribute to anxiety, depression, and subjective distress.^ Select subscales on the Omnibus Personality Inventory (OPI) were the operationalized measures for the personality component of the dimensions studied. An environmental index was developed to assess students' perceptions of the learning environment on these same dimensions. The Beck Depression Inventory, State-Trait Anxiety Inventory and General Well-Being schedule measured the outcome variables.^ A congruence model was employed to determine person-environment (P-E) interaction. Scores on the scales of the OPI and the environmental index were divided into high, medium, and low based on the range of scores. Congruence was defined as a match between the level of personality need and the complementary level of the perception of the environment. Alternatively, incongruence was defined as a mismatch between the person and the environment. The consistent category was compared to the inconsistent categories by an analysis of variance procedure. Furthermore, analyses of covariance were conducted with perceived supportiveness of the learning environment and life events external to the learning environment as the covariates. These factors were considered critical influences affecting the outcome measures.^ One hundred and eighty-five students (49% of the population) at the College of Optometry at the University of Houston participated in the study. Students in all four years of the program were equally represented in the study. However, the sample differed from the total population on representation by sex, marital status, and undergraduate major.^ The results of the study did not support the hypotheses. Further, after having adjusted for perceived supportiveness and life events external to the learning environment, there were no statistically significant differences between the congruent category and incongruent categories. Means indicated than the study sample experienced significantly lower depression and subjective distress than the normative samples.^ Results are interpreted in light of their utility for future study design in the investigation of the effects of P-E interaction. Emphasized is the question of the feasibility of testing a P-E interaction model with extant groups. Recommendations for subsequent research are proposed in light of the exploratory nature of the methodology. ^

Evaluating the Utility of Clinical Criteria for the Identification of Lynch Syndrome among Endometrial Cancer Patients

Background: Lynch Syndrome (LS) is a familial cancer syndrome with a high prevalence of colorectal and endometrial carcinomas among affected family members. Clinical criteria, developed from information obtained from familial colorectal cancer registries, have been generated to identify individuals at elevated risk for having LS. In 2007, the Society of Gynecologic Oncology (SGO) codified criteria to assist in identifying women presenting with gynecologic cancers at elevated risk for having LS. These criteria have not been validated in a population-based setting. Materials and Methods: We retrospectively identified 412, unselected endometrial cancer cases. Clinical and pathologic information were obtained from the electronic medical record, and all tumors were tested for expression of the DNA mismatch repair proteins through immunohistochemistry. Tumors exhibiting loss of MSH2, MSH6 and PMS2 were designated as probable Lynch Syndrome (PLS). For tumors exhibiting immunohistochemical loss of MLH1, we used the PCR-based MLH1 methylation assay to delineate PLS tumors from sporadic tumors. Samples lacking methylation of the MLH1 promoter were also designated as PLS. The sensitivity and specificity for SGO criteria for detecting PLS tumors was calculated. We compared clinical and pathologic features of sporadic tumors and PLS tumors. A simplified cost-effectiveness analysis was also performed comparing the direct costs of utilizing SGO criteria vs. universal tumor testing. Results: In our cohort, 43/408 (10.5%) of endometrial carcinomas were designated as PLS. The sensitivity and specificity of SGO criteria to identify PLS cases were 32.7 and 77%, respectively. Multivariate analysis of clinical and pathologic parameters failed to identify statistically significant differences between sporadic and PLS tumors with the exception of tumors arising from the lower uterine segment. These tumors were more likely to occur in PLS tumors. Cost-effectiveness analysis showed clinical criteria and universal testing strategies cost $6,235.27/PLS case identified and $5,970.38/PLS case identified, respectively. Conclusions: SGO 5-10% criteria successfully identify PLS cases among women who are young or have significant family history of LS related tumors. However, a larger proportion of PLS cases occurring at older ages with less significant family history are not detected by this screening strategy. Compared to SGO clinical criteria, universal tumor testing is a cost effective strategy to identify women presenting with endometrial cancer who are at elevated risk for having LS.

La organización territorial del movimiento de trabajadores desocupados Aníbal Verón del barrio Malvinas de la ciudad de La Plata

Este trabajo sintetiza los resultados de un estudio de campo realizado en la Organización Territorial del Movimiento de Trabajadores Desocupados Aníbal Verón del Barrio Malvinas de la ciudad de La Plata, entre el mes de Marzo del año 2003 (momento en el cual la Organización Territorial comienza sus actividades en el barrio y se incorpora, paulatinamente, al Movimiento de Trabajadores Desocupados Aníbal Verón) y los primeros meses del año 2005, cuando esta Organización conforma, junto a otras, el Frente Popular Darío Santillán. Los principales temas aquí desarrollados están relacionados, en principio, con la novedosa forma de participación político-comunitaria que insertó esta Organización Territorial en un barrio como Malvinas donde predominaban, desde hacía más de veinte años, formas de participación político-comunitarias de tipo clientelar. Otro de los temas aquí abordados está relacionado con los vínculos existentes entre la Organización Territorial y el Movimiento Regional. En esta trama vincular, se observó un desfasaje entre los criterios y acuerdos propuestos por el movimiento y las prácticas político-comunitarias llevadas adelante por la organización y los vecinos del barrio. Por último, en esta investigación también son centrales los distintos tipos de actores que interpretaban al movimiento de diferente manera. Aquí se observaron diversas formas de actuar, participar y comprometerse. En aquel momento, esto me llevó a proponer el armado de una tipología de participación de la que se desprende que la participación de los integrantes de la Organización Territorial del MTD Aníbal Verón del Barrio Malvinas, entre el año 2003 y 2005 era directa, inestable y complementaria. Lo que hacía que se fuera modificando con el propio devenir de la organización en movimiento. Es un trabajo más bien empírico y se nutrió por un lado, de datos obtenidos de entrevistas y observaciones realizadas para dos proyectos de extensión en los cuales participé y por otro, del trabajo de campo realizado entre el mes de Junio del año 2003 y Marzo del año 2005. El trabajo de campo constó de observaciones participantes y no participantes y, de entrevistas a los integrantes de la organización territorial. Entre el mes de octubre del año 2003 y el mes de enero del año 2004 realicé veinte entrevistas en profundidad. Para su realización se tomaron cuotas por sexo y edad hasta agotar información

ERA-interim reanalysis debiased at FLUXNET sites

(preliminary) Exchanges of carbon, water and energy between the land surface and the atmosphere are monitored by eddy covariance technique at the ecosystem level. Currently, the FLUXNET database contains more than 500 sites registered and up to 250 of them sharing data (Free Fair Use dataset). Many modelling groups use the FLUXNET dataset for evaluating ecosystem model's performances but it requires uninterrupted time series for the meteorological variables used as input. Because original in-situ data often contain gaps, from very short (few hours) up to relatively long (some months), we develop a new and robust method for filling the gaps in meteorological data measured at site level. Our approach has the benefit of making use of continuous data available globally (ERA-interim) and high temporal resolution spanning from 1989 to today. These data are however not measured at site level and for this reason a method to downscale and correct the ERA-interim data is needed. We apply this method on the level 4 data (L4) from the LaThuile collection, freely available after registration under a Fair-Use policy. The performances of the developed method vary across sites and are also function of the meteorological variable. On average overall sites, the bias correction leads to cancel from 10% to 36% of the initial mismatch between in-situ and ERA-interim data, depending of the meteorological variable considered. In comparison to the internal variability of the in-situ data, the root mean square error (RMSE) between the in-situ data and the un-biased ERA-I data remains relatively large (on average overall sites, from 27% to 76% of the standard deviation of in-situ data, depending of the meteorological variable considered). The performance of the method remains low for the Wind Speed field, in particular regarding its capacity to conserve a standard deviation similar to the one measured at FLUXNET stations.

La organización territorial del movimiento de trabajadores desocupados Aníbal Verón del barrio Malvinas de la ciudad de La Plata

Este trabajo sintetiza los resultados de un estudio de campo realizado en la Organización Territorial del Movimiento de Trabajadores Desocupados Aníbal Verón del Barrio Malvinas de la ciudad de La Plata, entre el mes de Marzo del año 2003 (momento en el cual la Organización Territorial comienza sus actividades en el barrio y se incorpora, paulatinamente, al Movimiento de Trabajadores Desocupados Aníbal Verón) y los primeros meses del año 2005, cuando esta Organización conforma, junto a otras, el Frente Popular Darío Santillán. Los principales temas aquí desarrollados están relacionados, en principio, con la novedosa forma de participación político-comunitaria que insertó esta Organización Territorial en un barrio como Malvinas donde predominaban, desde hacía más de veinte años, formas de participación político-comunitarias de tipo clientelar. Otro de los temas aquí abordados está relacionado con los vínculos existentes entre la Organización Territorial y el Movimiento Regional. En esta trama vincular, se observó un desfasaje entre los criterios y acuerdos propuestos por el movimiento y las prácticas político-comunitarias llevadas adelante por la organización y los vecinos del barrio. Por último, en esta investigación también son centrales los distintos tipos de actores que interpretaban al movimiento de diferente manera. Aquí se observaron diversas formas de actuar, participar y comprometerse. En aquel momento, esto me llevó a proponer el armado de una tipología de participación de la que se desprende que la participación de los integrantes de la Organización Territorial del MTD Aníbal Verón del Barrio Malvinas, entre el año 2003 y 2005 era directa, inestable y complementaria. Lo que hacía que se fuera modificando con el propio devenir de la organización en movimiento. Es un trabajo más bien empírico y se nutrió por un lado, de datos obtenidos de entrevistas y observaciones realizadas para dos proyectos de extensión en los cuales participé y por otro, del trabajo de campo realizado entre el mes de Junio del año 2003 y Marzo del año 2005. El trabajo de campo constó de observaciones participantes y no participantes y, de entrevistas a los integrantes de la organización territorial. Entre el mes de octubre del año 2003 y el mes de enero del año 2004 realicé veinte entrevistas en profundidad. Para su realización se tomaron cuotas por sexo y edad hasta agotar información

La organización territorial del movimiento de trabajadores desocupados Aníbal Verón del barrio Malvinas de la ciudad de La Plata

Este trabajo sintetiza los resultados de un estudio de campo realizado en la Organización Territorial del Movimiento de Trabajadores Desocupados Aníbal Verón del Barrio Malvinas de la ciudad de La Plata, entre el mes de Marzo del año 2003 (momento en el cual la Organización Territorial comienza sus actividades en el barrio y se incorpora, paulatinamente, al Movimiento de Trabajadores Desocupados Aníbal Verón) y los primeros meses del año 2005, cuando esta Organización conforma, junto a otras, el Frente Popular Darío Santillán. Los principales temas aquí desarrollados están relacionados, en principio, con la novedosa forma de participación político-comunitaria que insertó esta Organización Territorial en un barrio como Malvinas donde predominaban, desde hacía más de veinte años, formas de participación político-comunitarias de tipo clientelar. Otro de los temas aquí abordados está relacionado con los vínculos existentes entre la Organización Territorial y el Movimiento Regional. En esta trama vincular, se observó un desfasaje entre los criterios y acuerdos propuestos por el movimiento y las prácticas político-comunitarias llevadas adelante por la organización y los vecinos del barrio. Por último, en esta investigación también son centrales los distintos tipos de actores que interpretaban al movimiento de diferente manera. Aquí se observaron diversas formas de actuar, participar y comprometerse. En aquel momento, esto me llevó a proponer el armado de una tipología de participación de la que se desprende que la participación de los integrantes de la Organización Territorial del MTD Aníbal Verón del Barrio Malvinas, entre el año 2003 y 2005 era directa, inestable y complementaria. Lo que hacía que se fuera modificando con el propio devenir de la organización en movimiento. Es un trabajo más bien empírico y se nutrió por un lado, de datos obtenidos de entrevistas y observaciones realizadas para dos proyectos de extensión en los cuales participé y por otro, del trabajo de campo realizado entre el mes de Junio del año 2003 y Marzo del año 2005. El trabajo de campo constó de observaciones participantes y no participantes y, de entrevistas a los integrantes de la organización territorial. Entre el mes de octubre del año 2003 y el mes de enero del año 2004 realicé veinte entrevistas en profundidad. Para su realización se tomaron cuotas por sexo y edad hasta agotar información

Strontium concentrations and isotopic compositions of anhydrites from the TAG active mound

Sr isotope analyses have been conducted on anhydrite samples from the TAG (Trans-Atlantic Geotraverse) active hydrothermal mound (26°08?N, Mid-Atlantic Ridge) that have previously been shown to exhibit two distinct patterns of REE behavior when normalized to TAG end-member hydrothermal fluid. Despite differences in REE patterns, the Sr isotope data indicate that all the anhydrites precipitated from fluids with a similar range of hydrothermal fluid and seawater components, and all but one were seawater-dominated (52%-75%). Speciation calculations using the EQ3/6 software package for geochemical modeling of aqueous systems suggest that the REE complexation behavior in different fluid mixing scenarios can explain the variations in the REE patterns. Anhydrites that exhibit relatively flat REE patterns [(La_bs)/(Yb_bs) = 0.8-2.0; subscript bs indicates normalization to end-member black smoker hydrothermal fluid] and a small or no Eu anomaly [(Eu_bs)/(Eu*_bs) = 0.8-2.0] are inferred to have precipitated from mixes of end-member hydrothermal fluid and cold seawater. REE complexes with hard ligands (e.g., fluoride and chloride) are less stable at low temperatures and trivalent Eu has an ionic radius similar to that of Ca2+ and the other REE, and so they behave coherently. In contrast, anhydrites that exhibit slight LREE-depletion [(La_bs)/(Yb_bs) = 0.4-1.4] and a distinct negative anomaly [(Eu_bs)/(Eu*_bs) = 0.2-0.8] are inferred to have precipitated from mixes of end-member hydrothermal fluid and conductively heated seawater. The LREE depletion results from the presence of very stable LREE chloro-complexes that effectively limit the availability of the LREE for partitioning into anhydrite. Above 250°C, Eu is present only in divalent form as chloride complexes, and discrimination against Eu2+ is likely due to both the mismatch in ionic radii between Eu2+ and Ca2+, and the strong chloro-complexation of divalent Eu which promotes stability in the fluid and inhibits partitioning of Eu2+ into precipitating anhydrite. These variations in REE behavior attest to rapid fluctuations in thermal regime, fluid flow and mixing in the subsurface of the TAG mound that give rise to heterogeneity in the formation conditions of individual anhydrite crystals.