Molecular genetics of gynecologic cancer.

During the past decades, the expansion of molecular biology has had a pivotal role in understanding the basis of cancer development and progression. In addition, real advances have been made in the application of DNA recombinant technology to cancer therapy and patient management. In gynecologic oncologic fields, there are also many investigations to explore the basic pathogenesis of gynecologic cancer, such as cervical cancer, ovarian cancer, and endometrial cancer. It is now known that specific types of human papilloma virus (HPV) are the principal etiologic agents for both cervical cancer and its precursors. However, the various kinds of alterations in oncogenes and tumor suppressor genes may play additional roles in carcinogenesis of cervical cancer. Although ovarian carcinoma is the most frequent cause of death from gynecologic malignancies, the histogenesis and biological characteristics of these tumors are not well understood. During the last several years, many key observations have been made concerning the genetic alterations associated with ovarian cancer. Recent researches including some dominant oncogenes and tumor suppressor gene mutations common to these malignancies are providing bases to elucidate the mechanisms underlying this cancer. The most important basis of endometrial cancer is that K-ras and p53 mutations are also frequently observed.     

Deformity correction of knee and leg lengthening by Ilizarov method in hypophosphatemic rickets: outcomes and significance of serum phosphate level

The authors evaluated 14 patients with hypophosphatemic rickets who underwent correction of a knee deformity along with a leg lengthening by the Ilizarov method. Deformity correction alone was performed in 8 femora and 4 tibiae-fibulae, and concomitant deformity correction and limb lengthening (>1.0 cm) in 9 femora and 19 tibiae-fibulae. The healing index correlated with the biochemical parameters. Knee deformities were satisfactorily corrected in all patients except one. There was a statistically significant negative correlation between the healing index and the serum phosphate level: those who had a serum phosphate level higher than 2.5 mg/dL showed a relatively rapid regenerate bone healing compared with those with less than 2.5 mg/dL. The authors conclude that a serum phosphate level of 2.5 mg/dL as a cut-off point should be considered in deciding whether deformity correction alone or with a concomitant leg lengthening should be undertaken.     

PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway.

The PTEN tumor suppressor is frequently mutated in human tumors. Loss of PTEN function is associated with constitutive survival signaling through the phosphatidylinositol-3 kinase/Akt pathway. Therefore, we asked if reconstitution of PTEN function would lead to the reversal of resistance to apoptosis in prostate cancer cells. Adenovirus-mediated expression of PTEN completely suppressed constitutive Akt activation in LNCaP prostate cancer cells and enhanced apoptosis induced by a broad range of apoptotic stimuli. PTEN expression sensitized cells to death receptor-mediated apoptosis induced by tumor necrosis factor, anti-Fas antibody, and TRAIL. PTEN also sensitized cells to non-receptor mediated apoptosis induced by a kinase inhibitor staurosporine and chemotherapeutic agents mitoxantrone and etoposide. PTEN-mediated apoptosis was accompanied by caspase-3 and caspase-8 activation and was inhibited by a broad specificity caspase inhibitor Z-VAD-fmk. Bcl-2 overexpression also blocked PTEN-mediated apoptosis. Lipid phosphatase activity of PTEN is required for apoptosis as the PTEN G129E mutant selectively deficient in lipid phosphatase activity was unable to sensitize cells to apoptosis. PTEN-mediated apoptosis involves a FADD-dependent pathway for both death receptor-mediated and drug-induced apoptosis as coexpression of a dominant negative FADD mutant blocked PTEN-mediated apoptosis. Since in death receptor signaling, FADD mediates activation of caspase-8, which in turn cleaves BID, and since caspase-8 is activated in PTEN-mediated apoptosis, we examined BID cleavage in PTEN-mediated apoptosis. PTEN facilitated BID cleavage after treatment with low doses of staurosporine and mitoxantrone. BID cleavage was inhibited by dominant negative FADD. Taken together, these data are consistent with the hypothesis that PTEN promotes drug-induced apoptosis by facilitating caspase-8 activation and BID cleavage through a FADD-dependent pathway.     

Enriched feeding formula and immune responses and outcome after Listeria monocytogenes challenge in mice.

Immunocompromised malnourished patients are at high risk of developing serious opportunistic infection. This study examined the effect of feeding a special nutrient-enriched formula (Immun-Aid) on immune responses and mortality in mice challenged with Listeria monocytogenes. Two protocols were followed. In the first protocol, the animals were challenged with microorganisms when the experimental formula was introduced as the sole source of their nutrition. There was no significant effect on total T-lymphocyte number, but the proportion of helper T cells increased by day 7, resulting in a higher helper/suppressor (H/S) T lymphocyte ratio as well. Response to the mitogen phytohemagglutinin (PHA) was slightly higher on day 3 but came down and was comparable with that of control animals by day 7. Natural killer cell activity was slightly higher on day 7. Other immunologic parameters were unchanged. There was no significant difference in mortality between the two groups. In the second protocol, the animals were fed the experimental diet for 7 days before the infectious challenge. There was a slight increase in the total number of T lymphocytes on day 7. The numbers of helper and suppressor T lymphocytes were unchanged, but H/S was slightly higher on day 3 in the experimental group. Response to PHA was again higher on day 3 but plateaued on day 7. Natural killer cell activity was not altered. Mortality after infectious challenge was slightly but significantly decreased in the group of animals fed the enriched special formula. These results indicate a slight enhancement of selected parameters of immunity in mice fed the specially enriched formula and show that prior feeding with this formula for several days may partly protect against infectious challenge, resulting in reduced mortality.     

High-dose intravenous immunoglobulin downregulates the activated levels of inflammatory indices except erythrocyte sedimentation rate in acute stage of Kawasaki Disease

We evaluated the effects of high-dose intravenous immunoglobulin (IVIG) administration on various protein parameters, including inflammatory profiles, in children with Kawasaki disease (KD). Sixty-three children with KD were treated with IVIG at 2 g/kg over 12 h. Serial examinations of laboratory indices were performed three times: before IVIG treatment, 24 h after IVIG treatment, and 7 days after IVIG treatment. The white blood cell and neutrophil counts showed significant decreases 24 h and 7 days after IVIG administration. The erythrocyte sedimentation rate (ESR) increased significantly 24 h after IVIG, and the elevated level was sustained for 7 days. The levels of hemoglobin, albumin and inflammation-associated proteins, including C-reactive protein, decreased 24 h after IVIG treatment. Inflammation-associated proteins, except transferrin, decreased further to near normal levels after 7 days. On the other hand, IgM and IgA were not affected after 24 h, rather increased significantly after 7 days. High-dose IVIG causes immediate changes in the levels of various proteins, except IgA and IgM, and downregulates the activated levels of inflammatory indices, except ESR, in the acute stage of KD.     

Infant immune response to human rotavirus serotype G1 vaccine candidate reassortant WI79-9: different dose response patterns to virus surface proteins VP7 and VP4

BACKGROUND: Rotavirus is the leading cause of morbidity from gastroenteritis in the developed world and the leading cause of mortality from viral gastroenteritis (estimated 600000 deaths) worldwide. G1 is the most prevalent human serotype. Reassortant rotavirus between simian rotavirus RRV or bovine rotavirus WC3 and human strain rotaviruses have been extensively tested as candidate vaccines. Rotavirus (RV) reassortant strain WI79-9 consists of a human (strain WI79) G1 serotype VP7 surface protein on a bovine (strain WC3) background. It is a key component of a pentavalent (G1, G2, G3, G4 and P1) WC3 reassortant vaccine candidate, RotaTeq, now being tested in Phase III clinical trials. METHODS: We studied 84 infants between the ages of 2 and 8 months who received 3 oral doses of WI79-9. Serum neutralizing antibody was measured to the human (WI79 serotype P1 G1) and bovine (WC3 serotype P7 G6) parent RV after each dose. A significant response was defined as a > or =3-fold rise in antibody titer between the predose and postdose sera. RESULTS: In two separate cohorts of vaccinees given three doses of WI79-9 reassortant rotavirus, 68 to 75% of infants demonstrated a significant response to WC3 (VP4, P7) after Dose 1, fewer (24 to 39%) responses were detected after Dose 2 and rare (0 to 4%) additional responses occurred after Dose 3. The cumulative response rate to WC3 after three doses was 95% in both trials. In contrast 23 to 37% had a significant response to WI79 (VP7, G1) after Dose 1, and 57 to 61% had a significant response after Dose 2. Additional significant responses after Dose 3 led to a cumulative response of 70 to 84%. CONCLUSION: Two doses of G1 reassortant WI79 were necessary to induce significant antibody responses to human G1 (VP7) antigen in >50% of infants. Three doses were required to achieve significant antibody responses to VP7 in >70% of infants.     

Detection and characterization of focal hepatic lesions: mangafodipir vs. superparamagnetic iron oxide-enhanced magnetic resonance imaging

PURPOSE: To compare the mangafodipir-enhanced magnetic resonance (MR) and superparamagnetic iron oxide (SPIO)-enhanced images for their ability to detect and characterize focal hepatic lesions. MATERIALS AND METHODS: Unenhanced, mangafodipir-enhanced, and SPIO-enhanced hepatic MR images obtained from 64 patients were analyzed. A total of 121 hepatic lesions were included: 66 hepatocellular carcinomas (HCCs), 26 metastases, 14 hemangiomas, 5 cysts, 3 cholangiocarcinomas, 4 focal nodular hyperplasias (FNHs), 2 abscesses, and 1 adenoma. Two radiologists independently reviewed the two sets of images in a random order: 1) the unenhanced and mangafodipir-enhanced images (the mangafodipir set) and 2) the unenhanced and SPIO-enhanced images (the SPIO set). This study compared the accuracy of lesion detection, the ability to distinguish between a benign and malignant lesion, and the ability to distinguish between the hepatocellular and nonhepatocellular origins of the lesions using the areas (Az) under the receiver operating characteristic (ROC) curve. RESULTS: The overall accuracy for detecting focal lesions was significantly higher (P < 0.05) with the SPIO set (Az = 0.846 and 0.871 for readers 1 and 2, respectively) than with the mangafodipir set (Az = 0.716 and 0.766). Most of the lesions detected only with the SPIO-enhanced MR images by the readers were small HCCs. For lesions larger than 15 mm, the sensitivities of the two contrast enhancement techniques were similar for both readers. The accuracy of the mangafodipir and SPIO sets in distinguishing between benign and malignant lesions was comparable. The accuracy for distinguishing between the hepatocellular and nonhepatocellular origins of the lesions was significantly higher (P < 0.05) using the mangafodipir set (Az = 0.897 and 0.946) than using the SPIO set (Az = 0.741 and 0.833). CONCLUSION: SPIO- and mangafodipir-enhanced images were comparable for detection of focal hepatic lesions other than small HCCs, which were better detected on the SPIO-enhanced images. Mangafodipir-enhanced images are likely better than the SPIO-enhanced images for distinguishing between focal liver lesions with a hepatocellular or nonhepatocellular origin.