Role of ovarian cancer antigen CA125/MUC16 in development and cancer

Cancer antigen 125 (CA125) is a tumor antigen that is routinely used to monitor the disease progress and the outcome of treatment in ovarian cancer patients. Elevated serum levels of CA125 are detected in over 80% of epithelial ovarian cancer patients. CA125 is a high molecular weight (>1M Dalton) mucin-type glycoprotein encoded by the MUC16 gene on human chromosome 19. Although MUC16 has served as the best serum marker for monitoring growth of ovarian cancer, roles for MUC16 in normal physiology and ovarian cancer are largely unknown. To understand the biological functions of MUC16, I characterized a mouse Muc16 homolog on chromosome 9 by means of expression pattern profiling, phenotype analysis of Muc16 knockout mice, and in vitro and in vivo studies of Muc16 null transformed ovarian surface epithelial (OSE) cells. ^ The mouse Muc16 homolog shares a conserved genomic structure with human MUC16. In addition to being expressed in mouse ovarian cancer, mouse Muc16 mRNA and protein were expressed in the mesothelia covering the heart, lung, ovary, oviduct, spleen, testis, and uterus. The conserved genomic structure and expression pattern of mouse Muc16 to human MUC16 suggests that mouse Muc16 is the ortholog of human MUC16. To understand the biological functions of Muc16, I generated Muc16 knockout mice. Muc16 knockout mice were viable, fertile and normal by one year of age. However, between 18 and 24 months of age, Muc16 knockout mice developed various tissue abnormalities such as ovarian cysts and tumors of the liver and other peritoneal organs. To determine the role of MUC16 in ovarian cancer progression, I established Muc16 null transformed ovarian surface epithelial (OSE) cell lines, following the same method to develop mouse model of epithelial ovarian cancer (Orsulic et al., 2002). Loss of Muc16 did not affect cell morphology, cell proliferation rate, or tumorigenic potential. However, Muc16-null OSE cells showed decreased attachment to extracellular matrix proteins as well as to primary mouse peritoneal mesothelial cells. Peritoneal mesothelia are the most frequent implantation sites of ovarian cancer. Furthermore, a pilot transplantation assay suggests that Muc16 null transformed OSE cells formed less disseminated tumors in the peritoneal cavity compared to wild-type OSE cells. ^ In conclusion, these results demonstrate that MUC16 is not required for normal mouse development or reproduction, but plays important roles in tissue homeostasis, ovarian cancer cell adhesion and dissemination. This study provides the first in vivo evidence of the roles of MUC16 in development, as well as ovarian cancer progression and dissemination. These studies offer valuable insights into possible mechanisms of ovarian cancer development and potential molecular targets for ovarian cancer treatment. ^

A CASE-CONTROL STUDY OF RISK FACTORS FOR ECTOPIC PREGNANCY (ROCHESTER, MINNESOTA, OBSTETRICS)

A population-based case-control study of risk factors for ectopic pregnancy has been conducted. The investigation includes 274 cases diagnosed in Rochester, Minnesota residents from 1935 through 1982, and 548 matched controls selected from live birth deliveries. Risk factor information documented prior to the last index menstrual period was obtained via medical record abstract for 22 potential risk factor variables.^ Univariate matched analyses revealed nine variables with significantly elevated odds ratios (ORs). Following conditional logistic regression for matched sets, four variables remained as significant risk factors for ectopic pregnancy. These risk factors with ORs and 95% confidence intervals (Cls) were: current intrauterine device use (OR = 13.7, Cl = 1.6 - 120.6), infertility (OR = 2.6, Cl = 1.6 - 4.2), pelvic inflammatory disease (OR = 3.3, Cl = 1.6 - 6.6), and tubal surgery (OR = 4.5, Cl = 1.5 - 13.9). After adjusting for these four major risk factors, the following variables did not have statistically significant ORs: abdominal/pelvic surgery (OR = 2.0), acute appendicitis (OR = 2.0), anovulation (OR = 1.2), clomiphene citrate use during the index conception (OR = 3.5), induced abortion (OR = 2.1), in utero exposure to diethylstilbestrol (OR = 1.6), myomas (OR = 0.7), ovarian cysts (OR = 1.0), and past intrauterine device use (OR = 1.2). ^

A STUDY OF ILLNESS AND RESERVOIRS ASSOCIATED WITH GIARDIA LAMBLIA IN RURAL EGYPT

A longitudinal investigation of the health effects and reservoirs of Giardia lamblia was undertaken in forty households located in a rural Nile Delta region of Egypt. Stool specimens obtained once weekly for six months from two to four year old children were cyst or trophozoite-positive in 42 percent of the 724 examined. The mean duration of excretion in all but one Giardia-negative child was seven and one-half weeks with a range of one to 17 weeks. Clinical symptoms of illness were frequently observed within a month before or after Giardia excretion in stool of children, but a statistical inference of association was not demonstrated.^ Seventeen percent of 697 specimens obtained from their mothers was Giardia-positive for a mean duration of four weeks and a range of one to 18 weeks. Mothers were observed to excrete Giardia in stool less frequently during pregnancy than during lactation.^ Nine hundred sixty-two specimens were collected from 13 species of household livestock. Giardia was detected in a total of 22 specimens from cows, goats, sheep and one duck. Giardia cysts were detected in three of 899 samples of household drinking water.^ An ELISA technique of Giardia detection in human and animal stool was field tested under variable environmental conditions. The overall sensitivity of the assay of human specimens was 74 percent and specificity was 97 percent. These values for assay of animal specimens were 82 percent and 98 percent, respectively.^ Surface antigen studies reported from the NIH Laboratory of Parasitic Diseases show that antigens of three Egyptian human isolates are different from each other and from most other isolates against which they were tested.^ The ubiquity of human and animal fecal contamination combined with estimates of ill days per child per year in this setting are substantial arguments for the introduction of a suggested mass parasite control program to intervene in the cyclical transmission of agents of enteric disease. ^

Mid-Pliocene palynomorph record of the North Atlantic

The mid-Pliocene was an episode of prolonged global warmth and strong North Atlantic thermohaline circulation, interrupted briefly at circa 3.30 Ma by a global cooling event corresponding to marine isotope stage (MIS) M2. Paleoceanographic changes in the eastern North Atlantic have been reconstructed between circa 3.35 and 3.24 Ma at Deep Sea Drilling Project Site 610 and Integrated Ocean Drilling Program Site 1308. Mg/Ca ratios and d18O from Globigerina bulloides are used to reconstruct the temperature and relative salinity of surface waters, and dinoflagellate cyst assemblages are used to assess variability in the North Atlantic Current (NAC). Our sea surface temperature data indicate warm waters at both sites before and after MIS M2 but a cooling of ~2-3°C during MIS M2. A dinoflagellate cyst assemblage overturn marked by a decline in Operculodinium centrocarpum reflects a southward shift or slowdown of the NAC between circa 3.330 and 3.283 Ma, reducing northward heat transport 23-35 ka before the global ice volume maximum of MIS M2. This will have established conditions that ultimately allowed the Greenland ice sheet to expand, leading to the global cooling event at MIS M2. Comparison with an ice-rafted debris record excludes fresh water input via icebergs in the northeast Atlantic as a cause of NAC decline. The mechanism causing the temporary disruption of the NAC may be related to a brief reopening of the Panamanian Gateway at about this time.

Dinoflagellate cyst assemblages, oxygen isotope records of foraminifera, and alkenone and Mg/Ca-based SST estimates for the time interval 3.40-3.18 Ma (Late Pliocene) from five North Atlantic and Caribbean sediment cores

The early Late Pliocene (3.6 to ~3.0 million years ago) is the last extended interval in Earth's history when atmospheric CO2 concentrations were comparable to today's and global climate was warmer. Yet a severe global glaciation during marine isotope stage (MIS) M2 interrupted this phase of global warmth ~3.30 million years ago, and is seen as a premature attempt of the climate system to establish an ice-age world. Our geochemical and palynological records from five marine sediment cores along a Caribbean to eastern North Atlantic transect show that increased Pacific-to-Atlantic flow via the Central American Seaway weakened the North Atlantic Current (NAC) and attendant northward heat transport prior to MIS M2. The consequent cooling of the northern high latitude oceans permitted expansion of the Greenland ice sheet during MIS M2, despite near-modern atmospheric CO2 concentrations. Before and after MIS M2, heat transport via the NAC was crucial in maintaining warm climates comparable to those predicted for the end of this century.

New Pliocene and Pleistocene acritarchs from the North Atlantic, Arctic Ocean and Bering Sea

Acritarchs have received limited attention in palynological studies of the Cenozoic, although they have much potential both for refining Neogene and Quaternary stratigraphy, especially in mid- and high northern latitudes, and developing palaeoceanographical reconstructions. Here we formally describe and document the stratigraphical and palaeotemperature ranges (from foraminiferal Mg/Ca) of four new acritarch species: Cymatiosphaera? aegirii sp. nov., Cymatiosphaera? fensomei sp. nov., Cymatiosphaera? icenorum sp. nov. and Lavradosphaera canalis sp. nov. In reviewing the stratigraphical distributions of all species of the genus Lavradosphaera De Schepper & Head, 2008, we demonstrate their correlation potential between the North Atlantic and Bering Sea in the Pliocene. Additionally, Lavradosphaera lucifer De Schepper & Head, 2008 and Lavradosphaera canalis sp. nov., while not themselves overlapping stratigraphically, have morphological intermediates that do partially overlap and may represent an evolutionary trend consequent upon climate cooling in the Late Pliocene. Finally, we show that the highest abundances of the acritarchs presented here were living in the eastern North Atlantic, in surface-water temperatures not very different from today.

Calcareous dinoflagellate cycst in the mid-Cenomanian Boreal realm

A transect from the bathyal to proximal shelf facies of the Boreal Realm was investigated to compare spatial and temporal distribution changes of calcareous dinoflagellate cysts (c-dinocysts) throughout the mid-Cenomanian in order to gain information on the ecology of these organisms. Pithonelloideae dominated the cyst assemblages to more than 95% on the shelf, a prevalence that can be observed throughout most of the Upper Cretaceous. The affinity of this group with the dinoflagellates, which is still controversially discussed, can be confirmed, based on evidence from morphological features and distribution patterns. The consistent prevalence of Pithonella sphaerica and P. ovalis in c-dinocyst assemblages throughout the Upper Cretaceous indicates that they were produced more frequently than cysts of the other species and might, therefore, represent a vegetative dinoflagellate life stage. P. sphaerica and P. ovalis are interpreted as eutrophic species. P. sphaerica is the main species in a marginal-shelf upwelling area, offshore Fennoscandia. Here, sedimentary cyclicity appears to have been reduced to the strongest light/dark changes, while in the outer shelf sediments, light/dark cycles are well-developed and show pronounced temporal assemblage changes. Cyclic fluctuations in the P. sphaerica / P. ovalis ratio reflect shifts of the preferred facies zones and indicate changes in surface mixing patterns. During periods of enhanced surface mixing most parts of the shelf were well-ventilated, and nutrient-enriched surface waters led to high productivity and dominance of the Pithonelloideae. These conditions on the shelf contrasted with those in the open ocean, where more oligotrophic and probably stratified waters prevailed, and an assemblage with very few Pithonelloideae and dominance of Cubodinellum renei and Orthopithonella ? gustafsonii was characteristic. While orbitally-forced light/dark sedimentary cyclicity of the shelf sections was mainly related to surface-water carbonate productivity changes, no cyclic modulation of productivity was observed in the oceanic profile. Therefore, dark layer formation in the open ocean was predominantly controlled by the cyclic establishment of anoxic bottom water conditions. Orbitally-forced interruptions in mixing on the shelf resulted in cyclic periods of stratification and oligotrophy in the surface waters, an expansion of oceanic species to the outer shelf, and a shelfward shift of pithonelloid-facies zones, which were probably related to shelfward directed oceanic ingressions.

Dinoflagellate cyst counts and age model from sediment samples of ODP Hole 175-1085A

Sediment samples from ODP Site 1085 were investigated in order to obtain more information on the initiation and development of the Benguela upwelling system during the middle and upper Miocene. In particular, our intent was to establish the causes of the upwelling as well as the response of the upwelling regime to the development of the Antarctic Circumpolar Current. Based on changes in the calcareous dinoflagellate cyst association, we found an initial increase of the dinoflagellate cyst productivity, probably related to the initiation of upwelling about 11.8 Ma ago. Two distinct increases in cyst productivity in conjunction with temperature decreases of the upper water masses reflect upwelling pulses off Namibia and occur at the end of the Miocene cooling events Mi5 (about 11.5 Ma) and Mi6 (about 10.5 Ma). Both cooling events are associated with an ice volume increase in Antarctica and are thought to have led to an increase in southeasterly winds, possibly causing these two upwelling pulses. We demonstrate a decrease in dinoflagellate cyst productivity and enhanced terrigenous input via the Orange River after the Mi5 event. At about 11.1 Ma, the dinoflagellate cyst productivity increases again. The polar cyst species Caracomia arctica occurs here for the first time. This implies an influence of subantarctic mode water and therefore a change in the quality of the upwelling water which allowed the Benguela upwelling to develop into modern conditions. From about 10.4 Ma, C. arctica forms a permanent part of the association, pointing to an establishment of the upwelling regime.

(Table 1) Maceral composition and organic carbon chemistry of ODP Leg 104 samples

The Cenozoic sediments sampled in ODP Leg 104 on the Vøring Plateau show a distinct variability of the total organic carbon content (TOC) and the accumulation rates of TOC. Based on the geochemical and organic-petrographic characterization of the sedimentary organic matter (OM), the allochthonous and autochthonous proportion of the OM could be quantified. The results clearly demonstrate that high TOC percentages and TOC accumulation rates in Cenozoic sediment sections display a generally high input of allochthonous organic matter. Oxidized and partly well-rounded organic particles built up the main portion of OM within the Miocene, TOC-rich sediments. The most probable source of this oxidized OM are reworked sediments from the Scandinavian shelf. Changes in the input of these organic particles are to some degree correlative with sea-level changes. The Cenozoic accumulation of autochthonous OM is low and does not reveal a clear variation during the Miocene and early Pliocene. In spite of a high accumulation rate of biogenic opal during the Early Miocene, the accumulation rate of autochthonous TOC is low. The autochthonous particle assemblage is dominated by relatively inert OM, like dinoflagellate cysts. This points to an intensive biological and/or early diagenetic degradation of the marine OM under well oxidized bottom water conditions during the last 23 Myr. Nevertheless, a continuation of marine OM degradation during later stages of diagenesis cannot be excluded. A prominent dominance of allochthonous OM over autochthonous is documented with the beginning of the Pliocene. At 2.45 Ma the episodic occurrence of ice-rafted, thermally mature OM reflects the onset of the glacial erosion of Mesozoic, coal and black shale bearing sediments on the Scandinavian and Barents Sea shelves. The first occurrence of these, in view of the actual burial depth, thermally overmature OM particles is, therefore, a marker for the beginning of the strong Scandinavian glaciation and the advance of the glacial front toward the shelves.

Distribution of dinoflagellate cycst at ODP Site 123-765 (Table 1)

Site 765 contains a sequence of tropical, middle Miocene to Holocene dinoflagellate cysts. These diverse assemblages are characterized by abundant Polysphaeridium zoharyi and Spiniferites bulloideus. Abundances of Impagidinium spp. and Nematosphaeridium spp. reflect the shelf-to-slope origin of the assemblages. One new genus, Blysmatodinium, and two new species, Nematosphaeridium (?) wrennii sp. nov. and Blysmatodinium argoi, are described.

(Data S1) Palynological analysis of IODP and ODP sediment cores around the Antarctic margin

The circum-Antarctic Southern Ocean is an important region for global marine food webs and carbon cycling because of sea-ice formation and its unique plankton ecosystem. However, the mechanisms underlying the installation of this distinct ecosystem and the geological timing of its development remain unknown. Here, we show, on the basis of fossil marine dinoflagellate cyst records, that a major restructuring of the Southern Ocean plankton ecosystem occurred abruptly and concomitant with the first major Antarctic glaciation in the earliest Oligocene (~33.6 million years ago). This turnover marks a regime shift in zooplankton-phytoplankton interactions and community structure, which indicates the appearance of eutrophic and seasonally productive environments on the Antarctic margin. We conclude that earliest Oligocene cooling, ice-sheet expansion, and subsequent sea-ice formation were important drivers of biotic evolution in the Southern Ocean.

Monitoreo de parásitos patógenos en afluentes agroindustriales

Las aguas residuales son potenciales portadoras de enteroparásitos patógenos para el hombre cuya dosis infectiva puede ser mínima y prolongado el tiempo de sobrevivencia de huevos y quistes en el ambiente. La reglamentación limita la presencia de huevos de helmintos y, hasta el año 2000, no proponía una técnica para su detección. Este trabajo se realizó para caracterizar parasitológicamente los efluentes procedentes de agroindustrias. La capacitación en la identificación microscópica demandó la confección de fichas que describen las características de huevos de helmintos. Se efectuaron ensayos con muestras de bodegas y aceiteras en los puntos detectados de contaminación. Los métodos fueron adaptados a las particularidades de los efluentes. Los resultados no señalaron presencia de helmintos; no obstante, se hallaron Cyclospora e Isospora, protozoarios que, por su alto poder infectivo, también constituyen un riesgo para el hombre. Sin embargo, no están contemplados por la legislación. Respecto a helmintos, es necesario un estudio comparativo de las técnicas de detección para efluentes agroindustriales, con el fin de establecer las que optimicen su recuperación. En cuanto a otras especies es preciso continuar investigando su presencia para evaluar la conveniencia de incorporarlas a la reglamentación.