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Raloxifene reduces the size of leiomyomas in estradiol-exposed guinea pigs. Leiomyomas are fibroid tumors of the uterus, and they can develop from continuous high levels of estrogen in the body. Researchers placed estradiol-secreting implants in guinea pigs to induce leiomyoma formation, removed the implants, then replaced them. Some animals also received raloxifene, an estrogen blocking drug. The tumors grew in the presence of estradiol, regressed without estrogen stimulation, and regressed with simultaneous estradiol and raloxifene treatment. Leiomyomas appear to require estradiol exposure to continue growing, and raloxifene appears to block this process.

Argyrophilic nucleolar organizer regions (AgNOR) have been correlated with proliferative activity of neoplasms. Increased AgNOR may reflect increased proliferative activity of cells or ploidy. To explore this hypothesis, 41 breast carcinomas were processed for AgNOR silver staining and DNA flow cytometry. AgNOR counts were expressed as mean AgNOR/nucleus and percentage of tumor cells with more than five AgNOR/nucleus. The first count was designated mean AgNOR or mAgNOR, and the second count was designated AgNOR proliferative index or pAgNOR. Using Mantel-Haensel statistical analysis, carcinomas that exhibited mAgNOR of 2.4 or more had a high likelihood of aneuploidy (P < 0.0001), an S-phase fraction of more than 5.8% (P < 0.003), or a diameter greater than 2 cm (P < 0.007). In addition, tumors with pAgNOR of 8% or more showed a statistically significant correlation with aneuploidy (P < 0.004), tumor grade (P < 0.04), and a more significant one with high S-phase fraction (P < 0.0001). No significant correlation was obtained between pAgNOR and tumor size or lymph node status. These data indicate that AgNOR quantitation reflects changes in DNA ploidy and cell proliferation. They also suggest that the mean AgNOR counts correlate best with the DNA mass or ploidy and that the frequency of cells with higher AgNOR count best reflects proliferative activity or S-phase fraction. Cancer 1992; 69:1739-1744.

An extreme biomass burning event occurred in Indonesia from September through October 2015 due to severe drought conditions, partially caused by a major El Niño event, thereby allowing for significant burning of peatland that had been previously drained. This event had the highest sustained aerosol optical depths (AODs) ever monitored by the global Aerosol Robotic Network (AERONET). The newly developed AERONET Version 3 algorithms retain high AOD at the longer wavelengths when associated with high Ångström exponents (AEs), which thereby allowed for measurements of AOD at 675 nm as high as approximately 7, the upper limit of Sun photometry. Measured AEs at the highest monitored AOD levels were subsequently utilized to estimate instantaneous values of AOD at 550 nm in the range of 11 to 13, well beyond the upper measurement limit. Additionally, retrievals of complex refractive indices, size distributions, and single scattering albedos (SSAs) were obtained at much higher AOD levels than possible from almucantar scans due to the ability to perform retrievals at smaller solar zenith angles with new hybrid sky radiance scans. For retrievals made at the highest AOD levels the fine‐mode volume median radii were ~0.25–0.30 micron, which are very large particles for biomass burning. Very high SSA values (~0.975 from 440 to 1,020 nm) are consistent with the domination by smoldering combustion of peat burning. Estimates of the percentage peat contribution to total biomass burning aerosol based on retrieved SSA and laboratory measured peat SSA were ~80–85%, in excellent agreement with independent estimates. AERONET Version 3 screening allows many more AOD especially at longer wavelengths than Version 2 for very high smoke AOD conditionsRetrieved very high aerosol single scattering albedo and large fine‐mode particle size are consistent with aerosol dominated by peatland burningMODIS satellite retrieval algorithms of AOD (collection 6.1) screened out a significant number of high fine‐mode AOD days during the event

The cases of three patients whose ovarian cancer spread to the abdominal wall after laparoscopic examination are discussed. Laparoscopy uses a thin tube inserted into the abdomen to view pelvic organs. Two patients had laparoscopy to remove fluid from their abdomens and to remove samples from their pelvic areas for biopsy. The third patient had a cyst detected by ultrasound. Though the existence of small fluid-excreting cysts was noted during laparoscopy, a right ovarian biopsy and removal of the left ovary and fallopian tube were performed. Two weeks later, a 2 centimeter nodule and tumor deposits were found in the patient's abdomen in the area where the ovarian tissue had been extracted. The first two patients also developed masses in the area of the laparoscopy within two weeks of surgery. When ovarian cancer is suspected, laparoscopic procedures should not be performed.

Fallopian tube intraepithelial cancer is a postulated precursor of epithelial ovarian carcinomas. As research continues on epithelial ovarian carcinomas’ developmental pathways, representative tubal tissue must be procured for diagnostic, biological, and molecular studies without compromising pathological diagnosis.

I-kappa-B kinase e (IKBKE; IKKε) has been recently identified as a breast cancer oncogene, and its alteration appears to be an early event in breast cancer development. In this study, we demonstrated that IKKε is frequently overexpressed and activated in human ovarian cancer cell lines and primary tumors. Of 96 ovarian cancer specimens examined, 63 exhibited elevated levels of IKKε. Furthermore, alterations of IKKε were associated with late-stage and high-grade tumors, suggesting a role of IKKε in ovarian tumor progression rather than in tumor initiation. Overall survival in patients with elevated levels of IKKε was significantly lower than patients whose tumors expressed normal levels of IKKε. Moreover, both early and late-stage tumors that overexpressed IKKε conferred a poor prognosis, as compared with those that did not possess elevated IKKε levels. Notably, overexpression of IKKε rendered cells resistant to cisplatin, whereas knockdown of IKKε overcame cisplatin resistance in both A2780CP and C13 cells, which express high levels of endogenous IKKε. Therefore, these data demonstrate for the first time that deregulation of IKKε is a highly recurrent event in human ovarian cancer and could play a pivotal role in tumor progression and cisplatin resistance. IKKε could also serve as a prognostic marker and potential therapeutic target for this malignancy.

The role of aerosols in climate and climate change is one of the factors that is least understood at the present. Aerosols' direct interaction with solar radiation is a well understood mechanism that affects Earth's net radiative forcing. However, quantifying its magnitude is more problematic because of the temporal and spatial variability of aerosol particles. To enhance our understanding of the radiative effects of aerosols on the global climate, Singapore has joined the AERONET (Aerosol Robotic Network) worldwide network by contributing ground-based direct Sun measurements performed by means of a multiwavelength Sun-photometer instrument. Data are collected on an hourly basis, then are uploaded to be fully screened and quality assured by AERONET. We use a one year data record (level 1.5/2.0) of measured columnar atmospheric optical depth, spanning from November 2006 to October 2007, to study the monthly and seasonal variability of the aerosol optical depth and the Ångström exponent. We performed independent retrievals of these parameters (aerosol optical depth and Ångström exponent) by using the photometer's six available bands covering the near-UV to near-IR (380-1080 nm). As a validation, our independent retrievals were compared with AERONET 1.5/2.0 level direct Sun product.

An elastin-like polymer (ELP) was designed by genetic engineering techniques to mimic the extracellular matrix (ECM). The precise control of the polymer sequence offered many advantages that allowed the definition of distinct and specific domains. The cell attachment domain present in the sequence enhances the cell adhesion. Hexamethylene diisocyanate, a lysine-targeted crosslinker, was used to crosslink the purified polymer. The produced matrices presented an adequate mechanical performance and the morphological analysis by scanning electron microscopy show a homogeneous porous structure, ranging from nanometers to few micrometres. The biological tests will be assessed in future work. These results show the big potential of the ELPs in biomedical applications, especially in the development of systems for tissue engineering and drug release.

Water-leaving radiance, measured just above the ocean surface, contains important information about near-surface or subsurface processes that occur on or below the deep ocean and coastal water. As such, retrieving seawater inherent optical properties (IOPs) is an important step to determining water type, subsurface light field, turbidity, pigment concentration, and sediment loading. However, the retrieval (or inversion) of seawater IOPs from just above water radiance measurements is a multiparameter nonlinear problem that is difficult to solve by conventional optimization methods. The applicability of the simulated annealing algorithm (SA) is explored as a nonlinear global optimizer to solve this multiparameter retrieval problem. The SA algorithm is combined with widely known semianalytical relations for seawater's IOPs to parameter invert these properties from simulated and measured water-leaving reflectance spectra. Furthermore, given the versatility of the SA algorithm, the scheme is extended to retrieve water depth from input reflectance data. Extensive tests and comparisons with in situ and simulated data sets compiled by the International Ocean-Color Coordinating Group are presented. Field data include reflectance spectra acquired with a handheld GER 1500 spectroradiometer and absorption measurements, performed with the AC-9 instrument on waters around Singapore's nearby islands.

Ovarian cancer is the leading cause of death among gynecological malignancies in the US and the poor outcome of current treatments necessitates the development of novel therapeutic strategies to fight against it. Epidemiological data indicate a positive association between higher latitude and ovarian cancer incidence and mortality rates, suggesting that vitamin D insufficiency may contribute to ovarian cancer development. Recent studies in the authors' laboratory showed that multiple ovarian cancer cell lines respond to the active form of vitamin D, 1α,25-dihydroxyvitamin D3, for growth suppression. Mechanistic studies identified vitamin D-regulated genes with established functions in ovarian tumorigenesis as mediators for the growth suppression. While increased p27 protein stability and transcriptional up-regulation of GADD45 are responsible for 1α,25-dihydroxyvitamin D3-induced cell cycle arrest at G1/S and G2/M checkpoints, respectively, the hormone-induced apoptosis in ovarian cancer cells involves the down regulation of the mRNA stability of telomerase catalytic subunit. More importantly, preclinical studies showed that the synthetic vitamin D analog EB1089 effectively suppressed the growth of human ovarian tumor xenografts in mice. The tumor suppression is associated with an increase in apoptotic rate and a decrease in cell proliferation, suggesting that the molecular information can be translated into ovarian tumor suppression in animals. Based on these studies, we conclude that the vitamin D receptor that mediates these anti-tumor effects represents a novel molecular target for the development of new drugs for ovarian cancer. We predict that receptor-based drug discovery will lead to the successful development of more potent and safer vitamin D analogs for the treatment of this deadly disease.

The human ovarian surface epithelium (HOSE) is the putative source of ovarian epithelial cancer, the most lethal gynecologic malignancy that affects women in the United States. The current study was designed to provide a database of normal HOSE cell features for diagnostic and research applications. HOSE was harvested from 42 women undergoing laparoscopy or laparotomy for benign gynecologic disorders, infertility problems, or pregnancy. Of the 42 women, 12 were postovulatory and 20 were receiving hormonal regimens. Cells were harvested with a sterile brush inserted through a laparoscopic port or with a sterile cell scraper at laparotomy. Two HOSE populations were identified, ranging in size from 8 to 10 μm and from 15 to 20 μm, respectively. The cells measuring 15–20 μm exhibited slight anisonucleosis, more prominent nucleoli, fine cytoplasmic metachromasia, and an overall reparative or squamoid morphology. Cells were single or arranged in small clusters, sheets, or papillae. They coexpressed cytokeratin and vimentin but did not overexpress p53. Cellularity and proliferation (up to 3.2% ± 0.8) were higher and papillae more frequent in postovulatory and cyst-bearing ovaries, including polycystic ovaries, suggesting underlying ovarian or hormonal influences. Representative HOSE brushings yielded a mean of 23,133 cells per patient (range, 4250–64,500 cells), equivalent to an estimated 0.58, 0.46, and 0.14 μg of nuclear protein, cell RNA, and nuclear DNA, respectively. Within 7–10 days of explantation, HOSE cells formed confluent monolayers with immunohistochemical and ultrastructural epithelial features. The current study defined baseline features of HOSE cells important to pathologists and clinicians evaluating women at risk for ovarian epithelial cancer and to researchers investigating the pathobiology of this aggressive gynecologic malignancy. Cancer (Cancer Cytopathol) 2004;102:1–10. © 2003 American Cancer Society.

Normal cellular functions of hamartin and tuberin, encoded by the TSC1 and TSC2 tumor suppressor genes, are closely related to their direct interactions. However, the regulation of the hamartin-tuberin complex in the context of the physiologic role as tumor suppressor genes has not been documented. Here we show that insulin or insulin growth factor (IGF) 1 stimulates phosphorylation of tuberin, which is inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 but not by the mitogen-activated protein kinase inhibitor PD98059. Expression of constitutively active PI3K or active Akt, including Akt1 and Akt2, induces tuberin phosphorylation. We further demonstrate that Akt/PKB associates with hamartin-tuberin complexes, promoting phosphorylation of tuberin and increased degradation of hamartin-tuberin complexes. The ability to form complexes, however, is not blocked. Akt also inhibits tuberin-mediated degradation of p27(kip1), thereby promoting CDK2 activity and cellular proliferation. Our results indicate that tuberin is a direct physiological substrate of Akt and that phosphorylation of tuberin by PI3K/Akt is a major mechanism controlling hamartin-tuberin function.

Previous studies have demonstrated that AKT1 and AKT3 are activated by heat shock and oxidative stress via both phosphatidylinositol 3-kinase-dependent and -independent pathways. However, the activation and role of AKT2 in the stress response have not been fully elucidated. In this study, we show that AKT2 in epithelial cells is activated by UV-C irradiation, heat shock, and hyperosmolarity as well as by tumor necrosis factor α (TNFα) through a phosphatidylinositol 3-kinase-dependent pathway. The activation of AKT2 inhibits UV- and TNFα-induced c-Jun N-terminal kinase (JNK) and p38 activities that have been shown to be required for stress- and TNFα-induced programmed cell death. Moreover, AKT2 interacts with and phosphorylates IκB kinase α. The phosphorylation of IκB kinase α and activation of NFκB mediates AKT2 inhibition of JNK but not p38. Furthermore, phosphatidylinositol 3-kinase inhibitor or dominant negative AKT2 significantly enhances UV- and TNFα-induced apoptosis, whereas expression of constitutively active AKT2 inhibits programmed cell death in response to UV and TNFα stimulation with an accompanying decreased JNK and p38 activity. These results indicate that activated AKT2 protects epithelial cells from stress- and TNFα-induced apoptosis by inhibition of stress kinases and provide the first evidence that AKT inhibits stress kinase JNK through activation of the NFκB pathway.

Akt2 is a member of the Akt/PKB family, which is involved in a variety of cellular events including cell survival, proliferation, and differentiation. During skeletal muscle differentiation, the Akt2 but not Akt1 expression was significantly increased. Microinjection of anti-Akt2 but not anti-Akt1 antibody efficiently abrogated myogenesis, indicating that Akt2 plays a specific role in muscle differentiation. It has been well documented that ectopic expression of MyoD is sufficient to induce muscle differentiation in myoblasts. However, the mechanism of induction of Akt2 during muscle differentiation and the significance of Akt2 protein in MyoD-induced myogenesis are largely unknown. In this study, we provide direct evidence that Akt2is transcriptionally regulated by MyoD and activates MyoD-myocyte enhancer binding factor-2 (MEF2) transactivation activity. The Akt2promoter was isolated and found to contain nine putative E-boxes (CANNTG), which are putative MyoD binding sites. Electrophoretic mobility shift analyses revealed that MyoD bound to eight of the sites. The expression of MyoD significantly enhanced Akt2promoter activity and up-regulated Akt2 mRNA and protein levels. Moreover, Akt2 but not Akt1 was activated during differentiation. The expression of Akt2 activated MyoD-MEF2 transcriptional activity and induced myogenin expression. These data indicate that there is a positive feedback regulation loop between Akt2 and MyoD-MEF2 during muscle differentiation, which is essential for MyoD-induced myogenesis.

Hydrodechlorination of carbon tetrachloride was performed at atmospheric pressure over Pd and Pt catalysts supported on various inorganic oxides (Al 2 O 3 , MgO, CeO 2 ) and obtained from different organometallic precursors (Pd(acac) 2 , [Pd(C 3 H 5 )Cl] 2 , Pt(acac) 2 and Pt(CH 3 CN) 2 Cl 2 . Generally, Pd-based catalysts show low conversion levels and high selectivity to C 1 -C 7+ hydrocarbons with a distribution that fits a typical Schulz-Flory mechanism for alkyl polymerization. On the other hand, Pt catalysts show high and stable activity, the major products are CHCl 3 and in lesser extent methane. Catalytic performances depend on the stability, under reaction conditions, of the metal phase, that could be related to the nature of chlorine species pre-adsorbed on catalysts. Owning to their superior catalytic performances, the structural modifications of Pt catalysts under reaction conditions were characterized by EXAFS spectroscopy.

Extensive studies have demonstrated that the Akt/AKT1 pathway is essential for cell survival and inhibition of apoptosis; however, alterations of Akt/AKT1 in human primary tumors have not been well documented. In this report, significantly increased AKT1 kinase activity was detected in primary carcinomas of prostate (16 of 30), breast (19 of 50), and ovary (11 of 28). The results were confirmed by Western blot and immunohistochemical staining analyses with phospho-Ser473 Akt antibody. The majority of AKT1-activated tumors are high grade and stage III/lV (13 of 16 prostate, 15 of 19 breast, and 8 of 11 ovarian carcinomas). Previous studies showed that wild-type AKT1 was unable to transform NIH3T3 cells. To demonstrate the biological significance of AKT1 activation in human cancer, constitutively activated AKT1 (Myr-Akt) was introduced into NIH3T3 cells. Overexpression of Myr-Akt in the stably transfected cells resulted in malignant phenotype, as determined by growth in soft agar and tumor formation in nude mice. These data indicate that AKT1 kinase, which is frequently activated in human cancer, is a determinant in oncogenesis and a potential target for cancer intervention.

PTEN/MMAC1/TEP-1 (PTEN) tumor suppressor and androgen receptor play important roles in prostatic tumorigenesis by exerting opposite effects on homeostasis of prostatic epithelium. Here, we describe a mutual repression and selective dominance between PTEN and the androgen receptor (AR) in the growth and the apoptosis of prostatic cancer cells. On the one hand, PTEN and an inhibitor of phosphoinositide 3-kinase repressed the transcriptional activity of the AR as well as androgen-induced cell proliferation and production of prostate-specific antigen. On the other hand, androgens protected prostate cancer cells from PTEN-induced apoptosis in an AR-dependent manner. Whereas the repression of the transcriptional activity of the AR by PTEN is likely to involve the down-regulation of AKT, androgens protected prostate cancer cells from PTEN-induced apoptosis without an effect on AKT activity, demonstrating a differential involvement of AKT in the interaction between PTEN and the AR. Our data suggest that the loss of PTEN function may induce tumorigenesis through unopposed activity of the AR as well as contribute to the resistance of prostate cancers to androgen ablation therapy.

The Ru(II) complex [(sulphos)Ru(NCMe)3](OSO2CF3) (1) has been immobilized on partially dehydroxylated high-surface-area silica via hydrogen-bonding interactions between the silanol groups of the support and the SO3^- groups from both the sulphos ligand and the triflate counteranion (sulphos = ^-O3S(C6H4)CH2C(CH2PPh2)3). Compound 1 has been authenticated in the solid state by a single-crystal X-ray analysis and in solution by NMR spectroscopy, while its silica-grafted form [(sulphos)Ru(NCMe)3](OSO2CF3)/SiO2 (1/SiO2) has been characterized by DRIFT and CP MAS ³¹P NMR studies. The supported hydrogen-bonded (SHB) complex 1/SiO2 is an effective and selective catalyst for the hydrogenation of benzylideneacetone to benzylacetone and of benzonitrile to benzylidenebenzylamine in n-octane. No appreciable ruthenium leaching into the hydrocarbon phase was observed in either case. Analogous hydrogenation reactions catalyzed by either the aqueous-biphase catalyst 1 in water/n-octane or the homogeneous analogue [(triphos)Ru(NCMe)3](OSO2CF3)2 in THF have been carried out (triphos = MeC(CH2PPh2)3). The silica-supported catalyst is slightly less active but much more selective and recyclable than the soluble congeners. In an attempt to rationalize the selectivity exhibited by the SHB catalyst, various model studies have been performed in different phase variation systems. Incorporation of the results obtained led to the conclusion that, in contrast to fluid solution reactions, no heterolytic splitting of H2 at ruthenium occurs in the heterogeneous phase.

Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs that exhibit a remarkable ability to inhibit malignant transformation without toxicity to normal cells. However, the mechanism by which FTIs inhibit tumor growth is not well understood. Here, we demonstrate that FTI-277 inhibits phosphatidylinositol 3-OH kinase (PI 3-kinase)/AKT2-mediated growth factor- and adhesion-dependent survival pathways and induces apoptosis in human cancer cells that overexpress AKT2. Furthermore, overexpression of AKT2, but not oncogenic H-Ras, sensitizes NIH 3T3 cells to FTI-277, and a high serum level prevents FTI-277-induced apoptosis in H-Ras- but notAKT2-transformed NIH 3T3 cells. A constitutively active form of AKT2 rescues human cancer cells from FTI-277-induced apoptosis. FTI-277 inhibits insulin-like growth factor 1-induced PI 3-kinase and AKT2 activation and subsequent phosphorylation of the proapoptotic protein BAD. Integrin-dependent activation of AKT2 is also blocked by FTI-277. Thus, a mechanism for FTI inhibition of human tumor growth is by inducing apoptosis through inhibition of PI 3-kinase/AKT2-mediated cell survival and adhesion pathway.

PROBLEM: To determine the early effect of abdominal cytoreductive surgery on serum soluble interleukin‐2 receptor α (sIL‐2Rα) levels in patients with ovarian and cervical cancer, and to determine if the extent of cytoreduction correlated with the changes in serum sIL2Rα.

• Residual microscopic disease after lumpectomy for breast cancer may cause significant local recurrence. We evaluated one hundred fourteen consecutive breast lumpectomy margins in this study by touch preparation cytology. Cytologic preparations were intraoperatively correlated with gross and frozen section results and subsequently with permanent histologic sections of representative margins. Three specimens were cytologically unsatisfactory and 86 yielded benign findings, while material suggestive or diagnostic of malignancy was obtained from 25 specimens. Gross, frozen section, and permanent histologic margins were positive in 10, 17, and 22 cases, respectively. There were three false-positive touch preparation cytologic results, while frozen section specimens were false-negative in five cases. Sensitivity and specificity of touch preparation cytology were 100% and 96.6%, respectively, with a diagnostic accuracy of 97.3%. Touch preparation cytologic examination rapidly and reliably evaluates lumpectomy margins and overcomes sampling errors and artifacts related to frozen section evaluation. This technique currently complements frozen section evaluation of lumpectomy margins as part of a protocol aimed at reducing local recurrence of breast cancer.(Arch Surg. 1991;126:490-493)

Summary A method is described for dissection of endocervical folds from adult rabbits, and subsequent collagenase dissociation of these folds, to yield both a single cell suspension (mostly stromal elements) and epithelial segments (retained on a monofilament mesh filter).

Summary: This study analyzes the morphology and growth characteristics of rabbit ovarian mesothelial (surface epithelial) cells explanted in vitro. Best cell growth and expression of differentiation were obtained using a polystyrene substrate, 100 air, and a nutrient composed of 85 medium 199 and 15 fetal bovine serum. Surface epithelia gave rise to cell outgrowths within 36 h of explantation and formed confluent epithelial monolayers after 1 week. Cells exhibited a marked proliferative activity as indicated by: (a) a labeling index of 80 at day 4, and of 40 at days 10 and 38; (b) a cell doubling time of 30–36 h during the logarithmic phase of growth; and (c) an estimated 24 cell population doublings during 6 weeks. Confluent cultures contained cells cormplexed by desmosomes and tight junctions and displaying numerous microvillintracellular lumina, and focal cilia. Cells organized often into nests and gland like spaces and developed occasional hemicysts. High-density cultures developed also a multilayered configuration, villous processes, epithelial invaginations or crypts, and focal cytological features suggestive of steroidogenesis This study shows that rabbit ovarian surface epithelial cells can be maintained in vitro with a high degree of differentiation. This model is being used to investigate the pathobiology of ovarian surface epithelium.

The morphology of the ovarian mesothelium (surface epithelium) and of other pelvic and extrapelvic mesothelia was investigated in the rabbit by use of scanning electron microscopy. Villous processes of varied architectural complexity and surface epithelial crypts were found in the ovary but not in the mesothelial linings of the oviduct, uterus, liver, or pelvic and abdominal walls. Both ovarian and extraovarian mesothelial cells possessed abundant microvilli. Fully developed individual cilia and ciliary tufts were seen exclusively in ovarian mesothelia, while abortive or blunted cilia were rarely seen in pelvic but not in extrapelvic mesothelia. A distinct transition in surface configuration was present in contiguous mesothelia. In fact, ovarian mesothelia containing numerous villous processes, crypts, and cuboidal to low columnar cells merged with oviduct and fat mesothelia displaying only flat or low cuboidal cells. Villous processes were often lined by a stratified or pseu-dostratified epithelium and this histology resembled that of ovarian surface papillomas. Processes were more numerous in smaller ovaries than in larger ovaries where interstitial tissue and corpora lutea were prominent. This study underscores the unique architecture and morphogenetic behavior of the ovarian mesothelium. It also suggests that local factors and/or reproductive patterns may have a role in regulating the growth and development of this important ovarian component.

In this study we tested the hypothesis that estrogen affects the cytodifferentiation of endocervical cell types. Applying a unit gravity sedimentation procedure to pronase-dispersed endocervical cells, four cell types were isolated from estrous rabbits. Two of these cell types contained histochemically distinguishable (periodic acid-Schiff; PAS) glycoproteins and were designated vacuolated and granular PAS-positive cells. The third cell type, which did not contain secretory granules, was designated as vacuolated PAS-negative; the fourth cell population consisted of ciliated cells. These different cell populations and their biosynthetic capabilities were compared with endocervical cell populations from ovariectomized and ovariectomized estrogen-treated animals. As a result of ovariectomy, the endocervix was composed of ciliated cells and of a population of degranulated cells that were no longer involved in mucus glycoprotein biosynthesis, as indicated by negligible incorporation of a glycoprotein radiolabeled precursor ([14C]-N-acetyl-D-glucosamine). Estrogen administration (5 μg estradiol-17βanimal/12 h for 10 days) to ovariectomized rabbits resulted in the restoration of endocervical cell types whose morphological and biosynthetic characteristics were comparable to those of cells from estrous rabbits. Collectively, these data support the hypothesis that estrogen plays a significant role in maintaining both the cytoarchitecture and the biosynthetic activity of endocervical epithelium. This study also shows that the ovariectomized rabbit may represent a useful model in which to study the mechanism of estrogen action on endocervical mucus glycoprotein biosynthesis.

We evaluated the therapeutic value of sequential cyclical hormonal therapy (megestrol acetate, and tamoxifen citrate) plus single-agent chemotherapy (carboplatin) in the outpatient management of advanced or recurrent endometrial cancer. Carboplatin (300 mg/m2) was administered every 4 weeks for six courses or until disease progression. In addition, patients alternated megestrol acetate (80 mg orally twice daily) with tamoxifen citrate (20 mg orally twice daily) every 3 weeks. Thirteen of 18 (72.2%) patients were considered evaluable. Four patients (30.8%) had a complete response, six (46.2%) had a partial response, one (7.7%) had stable disease, and two patients (15.4%) progressed. Six of seven patients with vaginal disease responded. The median progression-free interval was 14 months for complete responders. Two patients (15.4%) are alive with no evidence of disease at 41 and 59 months. Seven of 13 patients experienced a hematologic toxicity (six grade 2, one grade 3); all resolved within 2 weeks. Dose reduction of carboplatin to 200 mg/m2was required in one patient. No other toxicities were encountered. The median survival for all patients is 11 months, and is 33 months for complete responders. We conclude that a regimen of carboplatin plus sequential hormonal therapy shows promise in this pilot study for the treatment of advanced or recurrent endometrial cancer.

A guinea pig model was used to study the hormonal control of uterine leiomyomas. Twenty female guinea pigs were divided into four groups—young, old, ovariectomized (OVX), and non-OVX animals—and were given two estradiol−17β (E2) silastic implants each for 3–10 mo; another four older OVX animals served as controls and received empty implants. After 3 mo, 100% (8 of 8) of the OVX animals, but none of the OVX controls, developed tumors, mainly on the uterine serosa and the abdominal wall. Electron microscopy and desmin immunostaining demonstrated that the tumors were leiomyomas. In E2-treated animals, E2levels in serum, leiomyomas, or leiomyoma-free uterine segments rose significantly while serum progesterone (P4) was negligible. Surprisingly, only 8% (1 of 12) of the non-OVX animals developed a tumor. This apparent “ovarian protection” was transient: after 6–9 mo, 50% of the remaining non-OVX animals developed leiomyomas, but these were smaller and fewer than in OVX animals.On the basis of this model, we propose the hypothesis that some factors from the ovaries suppress leiomyoma growth in response to estrogen but that as the ovaries age this protection is diminished, allowing the clinical development of leiomyomas.

Clostridium histolyticum collagenase, a noncytotoxic enzyme which is active in complete tissue culture medium at neutral pH was used successfully for achieving partial or total dissection of rabbit follicles from surrounding ovarian stroma. The procedure involved a 20 min incubation of ovarian slices in collagenase, 150 U/ml of culture medium containing 95 percent TCM199, 5 percent heat-inactivated rabbit serum and antibiotics. After washing, harvesting of follicles proceeded as follows: 1) washing solutions were centrifuged at 350 rpm for 5 min, the resulting pellet yielding 40–60 small primary follicles; 2) remaining ovarian slices were mechanically freed of incompletely dissected follicles under a stereomicroscope; this procedure yielded 80–100 large primary and secondary follicles. Light and electron microscopy showed cytostructural preservation and localization of the zone of separation between follicles and adjacent ovarian stroma at the granulosa- or theca externa-interstitial gland, and less frequently, at the theca interna-externa junctions. Occasionally, contamination of isolated follicles with 2–4 interstitial cells/follicle section was noted. Harvested follicles were divided into 6 morphologically different classes and characterized according to their size, protein, estrogen (E) and progesterone (P) content: small primary(127.05 µm ± 2.45; 2.30 µg ± 0.48; E, 26.59 pg ± 6.63; P, 24.21 pg ± 5.89); large primary(280.81 µm ± 8.92; 4.53 µg ± 0.80; E, 46.40 pg ± 4.91; P, 55.40 pg ± 16.35; small secondary(619.31 µm ± 21.88; 8.80 µg ± 2.00; E, 58.50 pg ± 12.57; P, 74.00 pg ± 19.62); large secondary(812.13 µm ± 25.40; 32.25 µg ± 8.13; E, 76.99 pg ± 33.79; P, 105.19 pg ± 28.48); small(≅150µm) and large atretic(478.00 µm ± 14.99; 15.73 µg ± 1.03; E, 66.59 pg ± 27.54; P, 104.33 pg ± 24.03). Total estrogen and progesterone follicular content increased progressively from small primary to large secondary follicles. Ultrastructurally, granulosa cells of harvested follicles displayed cytological features characteristic of active protein synthesis. Cytological features suggestive of steroid synthesis were predominantly seen in theca cells, increased progressively with follicular size and were particularly pronounced in large atretic follicles. Small atretic follicles contained a central core of lipid-rich cell debris and calcium deposits. A large perioocytic accumulation of calcospherules with frequent budding or fusion figures was often noted in large atretic follicles. This follicle isolation procedure was developed to provide baseline biochemical and morphological data at different stages of follicular development in preparation for the study of follicle maturation, regression and steroid secretion in organ culture.

This study was undertaken to determine if advanced epithelial ovarian cancer was associated with increased serum and ascitic levels of soluble interleukin-2 receptor α(sIL-2Rα). Serum and ascitic fluid samples from 23 ovarian cancer patients were analyzed for slL-2Rαusing an enzyme-linked immunosorbent assay and compared with the serum and peritoneal levels in 18 normal females. The samples were analyzed for CA-125 levels using a radioimmunoassay and the total protein was also measured. Normal individuals had low serum levels of slL-2Rα(367.5 ± 44.6 U/mL), with similar levels of slL-2Rαin the normal peritoneal fluid (438.6 ± 48.8 U/mL). In contrast, the serum and ascitic fluid levels in ovarian cancer patients were significantly higher (746.7 ± 82.9 U/mL, P= .0006; 2,656.7 ± 373.7 U/mL, P =.00002, respectively). The results for slL-2Rαwere also significant when the levels were expressed per milligram of total protein. More importantly, in almost every ovarian cancer patient the ascitic slL-2Rαlevel far exceeded the serum level, a pattern also observed for CA-125. There was no correlation between the serum and ascitic slL-2Rαlevels, or between the serum and ascitic CA-125 levels. Although the serum levels of slL-2Rαand CA-125 were elevated in the same patient, overall there was no correlation between the serum slL-2Rαand serum CA-125 levels, either when the levels were expressed in absolute units or per milligram of total protein. Similarly, there was no correlation between slL-2Rαand CA-125 levels in individual ascitic samples. While CA-125 levels may reflect an independent index of tumor burden, these results suggest that selective accumulation of slL-2Rαin the ascites may be one of the factors associated with the known nonresponsiveness of the infiltrating lymphocytes against ovarian carcinoma cells.

The manner in which estrogens mediate cyclical changes in the viscoelastic properties and volume of cervical mucus is unclear. To identify the response to estrogens of each of the major mucus components (mucin[s], soluble proteins, and small electrolytes and water), the authors quantitated their accumulation rates before and during estrogen stimulation in the rabbit. Circulating radiolabeled markers (35S-sulfate and 131I-albumin) were used to monitor the incorporation of small and large molecular weight intravascular substances into the cervical mucus. The accumulation rate of mucins was unaffected by exogenous estrogen administration, despite significant increases in mucus volume. This increase in mucus volume was attributed to a significantly increased transudation of water and small electrolytes increasing mucus hydration as early as the first 2 hours of estrogen administration. Water, small electrolytes, and soluble proteins significantly increased during the third and fourth hours of estrogen administration, not only when compared with the unstimulated basal levels, but also when compared with the levels found during the first 2 hours of estrogen administration. No significant change occurred in mucin production, while significant changes occurred in the accumulation of proteins and small electrolytes, whether estrogen was given initially or terminally in the experiment protocol.

Voided urine and bladder washing cytology are used frequently in the evaluation of transitional cell carcinoma of the bladder. As part of an ongoing investigation we report on the role of deoxyribonucleic acid (DNA) image analysis cytometry as an adjunct to cytology in the followup of patients with transitional cell carcinoma.

The ovarian mesothelium (OM) is the source of one of the most frequent and lethal types of common ovarian epithelial tumors, the so-called papillary serous carcinomas. Recent work from our laboratory indicates the existence of postovulatory luteal OM mitogens with variable affinity for heparin. To further investigate the paracrine regulation of this ovarian tissue, rabbit ovarian mesothelial cells (OMC) were cultured in serum-free, fibronectin-rich HL-1 medium with or without one of the following luteal growth factors (0.1, 1, and 10 ng/ml): basic (bFGF) and acidic (aFGF) fibroblastic growth factors, epidermal growth factor (EGF), transforming growth factors α (TGFα) and β (TGFβ), tumor necrosis factor α, platelet-derived growth factor (PDGF-BB), and vascular endothelial growth factor. After 8 days of culture, OMC growth was stimulated 3-fold by all tested doses of bFGF, EGF, and TGFα and 2–2.5-fold by 10 ng/ml of PDGF-BB and aFGF; it was inhibited more than 60% by TGFβ (10 ng/ml). In addition to enhancing the formation of cohesive OMC monolayers, most factors enhanced 3- to 6-fold the aggregation of OMC into papillary processes. The finding of a growth and morphogenetic response to intraluteal growth factors is novel and suggests a role for postovulatory paracrine regulation of OM pathobiology.

Morphologic studies suggest that the proliferative activity of the ovarian surface epithelium (OSE) may vary during the reproductive life cycle. To further investigate this phenomenon, rabbit ovaries obtained before and after induction of ovulation with human chorionic gonadotropin (hCG) were incubated in medium containing 3H-methylthymidine and processed for autoradiography. Before ovulation, the labeling index (LI) of OSE cells varied from 0.04% to 0.22%. Twelve hours after hCG, the maximal LI (9.02 ± 0.38%) was seen in OSE cells adjacent to the ovulatory stigma. The LI remained elevated at Days 1 and 5 post-hCG in OSE cells overlying corpora lutea. At Day 12, numerous papillary processes were observed at the apex of each corpus luteum. The maximal LI (16.44 ± 1.31%) had now shifted to the OSE cells covering these processes. Eighteen days after hCG stimulation, the LI of OSE cells near the corpora lutea had returned to preovulatory levels. A slight increase in the LI of OSE cells not associated with ovulatory sites was also observed after ovulation. This study shows that a significant fraction of OSE cells undergoes DNA synthesis throughout most of the postovulatory period.

Throughout life, the ovarian surface epithelium (OSE) undergoes morphogenetic changes that may be hormonally regulated. To investigate this possibility, a population of cells morphologically identical to native OSE cells was isolated from estrous rabbits with collagenase, unit gravity sedimentation, and trypsin-EDTA. Cells were incubated with various concentrations of protein hormones in serum-rich medium or in a chemically defined medium containing fibronectin. Tritiated thymidine was added 24 h before interruption of cultures. Growth-promoting effects of tested hormones were more pronounced and consistent in serum-free cultures. Under these conditions, human chorionic gonadotropin (10,000 mIU/ml) caused a 2.8-fold increase in cell number and a 3.4-fold stimulation of thymidine incorporation. Luteinizing hormone (NIAMDD-oLH-24, 1.0 μg/ml) and follicle-stimulating hormone (NIADDK-oFSH-16, 1.0 μg/ml) produced, respectively, a 1.7-fold and 1.5-fold increase in cell proliferation, and over 1.4-fold and 1.3-fold stimulations of thymidine uptake. When used together, no growth stimulation by these gonadotropins was seen. Slight but significant increases in cell number (1.4-fold) and in radiolabel incorporation (1.3-fold) were observed with prolactin (NIADDK-oPrl-16, 10 ng/ml). These data indicate that some protein hormones promote the growth of OSE cells. This property may be important in regulating these cells during normal and pathologic states.

Introduction:Rheumatic heart disease (RHD) is a sequela of a simple Group A streptococcal infection left untreated. It is estimated that in 2017 the global incidence of RHD was 1.3 million new cases up from 1.2 million cases in 2007. While most developed countries have access to screening and treatments, many countries are struggling with the global shortage of penicillin. Our study looks to identify the availability & cost of penicillin with the prevalence of RHD.Methods:Data from the Global Health Data Exchange (GHDx) was queried for incidence, prevalence, deaths, and disability years between the years of 2010-2017. We identified the 25/195 countries with the highest incidence, prevalence, and deaths due to RHD. We then identified the availability of penicillin. We used WHO, CDC, and international government agency websites to identify the costs of penicillin.Results:Using the GHDx we identified n= 195 countries in the world with reported data on RHD. We looked at the 25 countries that had the highest overall incidence. Of these countries, 11/25 reported shortage of antibiotics, 4/25 reported no shortage, and 5/25 had no report at all. The median price of penicillin is between $0.13 - $0.28.Discussion:The management of GAS infection is a simple shot of Benzathine Penicillin G (BPG) which can prevent the development of RHD at a rate of 80%. Our results show with decreased availability of Penicillin there is increased use of other antibiotics, which may not effectively treat the infection and lead to rheumatic fever or latent rheumatic heart disease. A solution we propose is for governments of these countries to incentivize pharmaceutical companies to produce antibiotics such as BPG. This will allow for a better supply chain and can prevent deaths from RHD. With the increased incidence of RHD and decreased supply of BPG, it is critical to identify solutions to curb unnecessary fatalities from RHD.Figures: