The detection, treatment, and biology of epithelial ovarian cancer

Ovarian cancer is particularly insidious in nature. Its ability to go undetected until late stages coupled with its non-descript signs and symptoms make it the seventh leading cause of cancer related deaths in women. Additionally, the lack of sensitive diagnostic tools and resistance to widely accepted chemotherapy regimens make ovarian cancer devastating to patients and families and frustrating to medical practitioners and researchers. Here, we provide an in-depth review of the theories describing the origin of ovarian cancer, molecular factors that influence its growth and development, and standard methods for detection and treatment. Special emphasis is focused on interactions between ovarian tumors and the innate and adaptive immune system and attempts that are currently underway to devise novel immunotherapeutic approaches for the treatment of ovarian tumors

Investigating the Cosmic-Ray Ionization Rate in the Galactic Diffuse Interstellar Medium through Observations of H3+

Observations of H3+ in the Galactic diffuse interstellar medium (ISM) have led to various surprising results, including the conclusion that the cosmic-ray ionization rate (zeta_2) is about 1 order of magnitude larger than previously thought. The present survey expands the sample of diffuse cloud sight lines with H3+ observations to 50, with detections in 21 of those. Ionization rates inferred from these observations are in the range (1.7+-1.3)x10^-16 s^-1<zeta_2<(10.6+-8.2)x10^-16 s^-1 with a mean value of zeta_2=(3.5^+5.3_-3.0)x10^-16 s^-1. Upper limits (3 sigma) derived from non-detections of H3+ are as low as zeta_2<0.4x10^-16 s^-1. These low upper-limits, in combination with the wide range of inferred cosmic-ray ionization rates, indicate variations in zeta_2 between different diffuse cloud sight lines. A study of zeta_2 versus N_H (total hydrogen column density) shows that the two parameters are not correlated for diffuse molecular cloud sight lines, but that the ionization rate decreases when N_H increases to values typical of dense molecular clouds. Both the difference in ionization rates between diffuse and dense clouds and the variation of zeta_2 among diffuse cloud sight lines are likely the result of particle propagation effects. The lower ionization rate in dense clouds is due to the inability of low-energy (few MeV) protons to penetrate such regions, while the ionization rate in diffuse clouds is controlled by the proximity of the observed cloud to a site of particle acceleration.Comment: 48 pages, 19 figures, 4 tables, accepted for publication in Ap

Investigating the Cosmic-Ray Ionization Rate Near the Supernova Remnant IC 443 Through H3+ Observations

Observational and theoretical evidence suggests that high-energy Galactic cosmic rays are primarily accelerated by supernova remnants. If also true for low-energy cosmic rays, the ionization rate near a supernova remnant should be higher than in the general Galactic interstellar medium (ISM). We have searched for H3+ absorption features in 6 sight lines which pass through molecular material near IC 443---a well-studied case of a supernova remnant interacting with its surrounding molecular material---for the purpose of inferring the cosmic-ray ionization rate in the region. In 2 of the sight lines (toward ALS 8828 and HD 254577) we find large H3+ column densities, N(H3+)~3*10^14 cm^-2, and deduce ionization rates of zeta_2~2*10^-15 s^-1, about 5 times larger than inferred toward average diffuse molecular cloud sight lines. However, the 3 sigma upper limits found for the other 4 sight lines are consistent with typical Galactic values. This wide range of ionization rates is likely the result of particle acceleration and propagation effects, which predict that the cosmic-ray spectrum and thus ionization rate should vary in and around the remnant. While we cannot determine if the H3+ absorption arises in post-shock (interior) or pre-shock (exterior) gas, the large inferred ionization rates suggest that IC 443 is in fact accelerating a large population of low-energy cosmic rays. Still, it is unclear whether this population can propagate far enough into the ISM to account for the ionization rate inferred in diffuse Galactic sight lines.Comment: 14 pages, 3 figures, 4 table

Terpenoids from Zingiber officinale (Ginger) Induce Apoptosis in Endometrial Cancer Cells through the Activation of p53

Novel strategies are necessary to improve chemotherapy response in advanced and recurrent endometrial cancer. Here, we demonstrate that terpenoids present in the Steam Distilled Extract of Ginger (SDGE) are potent inhibitors of proliferation of endometrial cancer cells. SDGE, isolated from six different batches of ginger rhizomes, consistently inhibited proliferation of the endometrial cancer cell lines Ishikawa and ECC-1 at IC50 of 1.25 mg/ml. SDGE also enhanced the anti-proliferative effect of radiation and cisplatin. Decreased proliferation of Ishikawa and ECC-1 cells was a direct result of SDGE-induced apoptosis as demonstrated by FITC-Annexin V staining and expression of cleaved caspase 3. GC/MS analysis identified a total of 22 different terpenoid compounds in SDGE, with the isomers neral and geranial constituting 30–40%. Citral, a mixture of neral and geranial inhibited the proliferation of Ishikawa and ECC-1 cells at an IC50 10 mM (2.3 mg/ml). Phenolic compounds such as gingerol and shogaol were not detected in SDGE and 6-gingerol was a weaker inhibitor of the proliferation of the endometrial cancer cells. SDGE was more effective in inducing cancer cell death than citral, suggesting that other terpenes present in SDGE were also contributing to endometrial cancer cell death. SDGE treatment resulted in a rapid and strong increase in intracellular calcium and a 20–40% decrease in the mitochondrial membrane potential. Ser-15 of p53 was phosphorylated after 15 min treatment of the cancer cells with SDGE. This increase in p53 was associated with 90% decrease in Bcl2 whereas no effect was observed on Bax. Inhibitor of p53, pifithrin-a, attenuated the anti-cancer effects of SDGE and apoptosis was also not observed in the p53neg SKOV-3 cells. Our studies demonstrate that terpenoids from SDGE mediate apoptosis by activating p53 and should be therefore be investigated as agents for the treatment of endometrial cancer

Citral inhibits proliferation of endometrial cancer cells.

<p>MTT assays were conducted to determine the effect of 6-gingerol (A and B) and citral (C and D) on the proliferation of Ishikawa and ECC-1 cells. Each data point is a mean of 16 individual readings. Based on this data the IC₅₀ of citral was calculated to be 15–25 µM.</p

SDGE mediates endometrial cancer cell apoptosis through the activation of p53.

<p>After treating Ishikawa cells with SDGE (250 ng/ml) for the designated time points, the cells were harvested and lysates were analyzed by Western blotting for expression of Bcl-2 and Bax (A). Phosphorylation of Ser-15 of p53 was monitored in Ishikawa cells treated with SDGE (250 ng/ml) (B). Ishikawa cells were incubated with SDGE in the presence or absence of pifithrin-α for 18 h. Control Ishikawa cells were not exposed to either SDGE or pifithrin-α. (C) Cells were harvested and apoptosis was measured by flow cytometry after staining with FITC-Annexin V and propidium iodide. Apoptosis in the p53^neg SKOV-3 cells after treatment with SDGE (250 ng/ml) was also measured by the FITC-Annexin V assay (D) or by monitoring the levels of cleaved Caspase3 by Western blotting (E) at the designated time intervals.</p

SDGE induces apoptosis in endometrial cancer cells.

<p>Ishikawa cells were treated with 250 ng/ml of SDGE for 30 min, 2 h, 4 h, and 16 h. After incubation with SDGE, cell survival was determined by labeling the cells with FITC-conjugated FITC-Annexin V and propidium iodide (A). The cells were analyzed by flow cytometry and cell death and apoptosis were identified as the events that were single positive for FITC-Annexin V (lower right quadrant) or double positive for both FITC-Annexin V and proidium iodide (upper right quadrant). SDGE-induced apoptotic cell death in the endometrial cancer cells was confirmed by detecting cleaved caspase 3 in western blot analysis (B). An increase in cleaved caspase 3 levels was observed when the Ishikawa cells were treated with SDGE (250 ng/ml) for 0, 24, 48, and 72 h. Data in A and B is representative of results obtained in three separate experiments,</p