Hypoxia inducible factor 2α/insulin-like growth factor receptor signal loop supports the proliferation and Oct-4 maintenance of mouse germline stem cells.

Hypoxia inducible factor 2α (HIF-2α) is critical for primordial germ cell (PGC) survival as knockout of HIF-2α (HIF-2α(-/-)) decreases both expression of Oct-4 and PGC number in genital ridge. Hypoxia is known to stabilize HIF-2α protein from proteasomal degradation. However, little is known about the hypoxia-associated endocrinal signaling in HIF-2α expression. The current work demonstrates a role for an endocrine insulin-like growth factor-I receptor (IGF-IR)-PI3K/Akt-mTOR-HIF-2α regulatory loop in the proliferation and Oct-4 maintenance of PGC-like alkaline phosphatase positive mouse germline stem cells (AP(+)GSCs). We found that hypoxia greatly increased the cell proliferation and the levels of nuclear Oct-4/HIF-2α protein of AP(+)GSCs. The hypoxic-AP(+)GSCs presented stronger stemness ability for germ cell differentiation than normoxic, with expressions of c-KIT (differentiation germ cell marker), VASA (differentiation germ cell marker) and SCP3 (meiotic marker) using a renal capsule transplantation assay. Meanwhile, hypoxia significantly increased the expression levels of secreted-IGF-I and IGF-IR. The IGF-I dose dependently increased the HIF-2α expression levels in AP(+)GSCs; and, the inhibition of IGF-IR by RNA interference (shIGF-IR) or LY294002 (PI3K inhibitor)/Rapamycin (mTOR inhibitor) effectively suppressed the IGF-I- and/or hypoxia-induced HIF-2α and Oct-4 expression, suggesting that the IGF-IR and its downstream Akt/mTOR signaling are involved in the IGF-I/hypoxia effects. Additionally, knockdown of HIF-2α dramatically suppressed Oct-4 and IGF-IR protein levels in AP(+)GSC cells. In conclusion, the present study demonstrates a regulatory loop of IGF-IR-PI3K/Akt-mTOR-HIF-2α in proliferation and Oct-4 maintenance of PGC-like AP(+)GSCs under hypoxia. This finding provides insights into the niche endocrinology underlying early germ cell development.

A whole genome methylation analysis of systemic lupus erythematosus: hypomethylation of the IL10 and IL1R2 promoters is associated with disease activity.

The etiology of systemic lupus erythematosus (SLE) involves a complex interaction of genetic and environmental factors. Investigations have shown that environmentally driven epigenetic changes contribute to the etiology of SLE. Here, we hypothesize that aberrant DNA methylation may contribute to the activation of the immune machinery and trigger lupus disease activity. A whole genome methylation array was applied to investigate the DNA methylation changes between 12 pairs of active SLE patients and healthy controls. The results were further confirmed in 66 SLE patients, 102 healthy controls. The methylation statuses of the IL10 and IL1R2 genes were significantly reduced in the SLE patient samples relative to the healthy controls (age-adjusted odds ratios, 64.2 and 16.9, respectively, P<0.0001). There was a trend toward SLE patients having hypomethylated IL10 and IL1R2 genes accompanied by greater disease activity. We observed that the methylation degree of IL10 and IL1R2 genes were reduced in the rheumatoid arthritis (RA) patients as well but the hypomethylation change was more significant in IL1R2 genes than in the IL10 genes in RA patients. This study demonstrated that DNA hypomethylation might be associated with SLE. Hypomethylated IL10 and IL1R2 genes may provide potential epigenetic markers as clinical predictors for autoimmune diseases.

Non-invasive prediction of skin flap shrinkage: a new concept based on animal experimental evidence.

A non-invasive, in vivo method has been developed to predict the skin flap shrinkage (retraction) following a harvest. It involves the use of a novel custom-designed extensometer to measure the force-displacement behaviour of skin and subsequent data analysis to estimate the shrinkage. In validation experiments performed on pigs, this method has been shown to produce results with an average absolute error of 6.0% between the actual and predicted shrinkages. This may be close to what an experienced surgeon would estimate subjectively, thus indicating the potential usefulness of this method to predict flap shrinkage of patient's donor sites.

New extensometer to measure in vivo uniaxial mechanical properties of human skin.

Biomechanical properties of skin are important for clinical decision making as well as clinical intervention. Measuring these properties in vivo is critical for estimating dimensional behaviour of skin flap or graft after harvest. However, existing methodologies and devices often suffer from lack of standardisation and unwanted peripheral force contribution due to the deformation of surrounding tissues during measurement. This naturally leads to measurement inaccuracies and lack of reproducibility. In order to improve the measurement accuracy, a new portable extensometer, which measures the non-invasive in vivo biomechanical properties of skin, has been designed and constructed. This design incorporates three pads that attach to the skin, including a C-shaped pad to shield the force sensor from peripheral forces. Such design produces data that are significantly closer to in vitro measurements. The results have been verified by finite element analysis, and experiments on rubber sheets and pig skins. This device can be used to obtain biomechanical properties of skin that will aid doctors in measuring skin elasticity and surgical planning, especially in skin flap surgery.

Warm or Cool, Large or Small? The Challenge of Thermal Displays.

Thermal displays have been developed to present thermal cues to the hand to facilitate object recognition in virtual environments or in teleoperated robotic systems. This review focuses on this application domain of thermal displays and considers the models developed to simulate the thermal interaction between an object and the hand as they make contact. An overview of thermal perception and the mechanisms underlying the processing of thermal information is provided to give a framework for analyzing the design of thermal displays. The models developed to simulate thermal feedback are examined together with a description of the implementation of these models in thermal displays. The domains in which thermal displays have been used are described; this includes the simulation of material properties, the recreation of large-scale thermal effects in virtual environments, the encoding of abstract concepts and the use of thermal feedback in interactive art. The review concludes by considering the advantages and challenges associated with using thermal displays in these diverse areas.

Derivation, characterization and differentiation of human embryonic stem cells: comparing serum-containing versus serum-free media and evidence of germ cell differentiation.

BACKGROUND: This study was designed to establish human embryonic stem cell (hESC) lines, to identify the differences when maintained in serum-containing versus serum-free medium and to test their potential of in vitro differentiation. METHODS: Procedures including immunosurgery were performed on 11 donated human blastocysts to establish hESC lines. The cell lines were characterized and maintained using either serum-free or serum-containing media to compare their morphology, Oct-4 expression, apoptosis and growth speed. Differentiation of these lines was evaluated by the morphology and the expression of genes belonging to the three embryonic germ layers and the germ cell lineage. RESULTS: Three hESC lines were established, and they grew at similar speed in both media (serum-containing or serum-free), but hESC cultured in serum-containing medium yielded significantly higher percentages of morphologically good colonies and cells expressing Oct-4. These cell lines differentiated spontaneously in vitro into cells expressing markers belonging to all three embryonic germ layers and germ cell markers, including c-Kit, STELLA, VASA and growth differentiation factor 9 (GDF9), in directly adherent culture. CONCLUSIONS: Three hESC lines with Taiwanese ancestry have been established, and they retain the in vitro differentiation potential with or without embryoid body (EB) formation. The data support that hESC may be capable of differentiation into germ cells although further confirmation is needed. It is also suggested that strategies such as stepwise adaptation will be needed before implementing a serum-free culture condition for hESC lines that have previously been derived in a medium containing serum.

Stellate transformation of invasive trophoblast: a distinct phenotype of trophoblast that is involved in decidual vascular remodelling and controlled invasion during pregnancy.

BACKGROUND: Successful implantation relies on the tightly regulated invasion of extravillous trophoblasts (EVTs). However, little is known about their phenotypic differentiation and relevant motile behaviour. Furthermore, the cell-cell interactions between EVTs and decidual arterioles during physiological transformation are also poorly understood. METHODS: A total of 128 decidual specimens from early and late gestations containing components of EVTs and spiral arterioles were investigated using immunohistochemistry and periodic acid-Schiff reaction. RESULTS: Unipolar, tadpole-like EVTs are observed throughout the interstitial area, with a tendency to decrease along the invasive pathway. The stellate differentiation of the EVTs is identified around and inside decidual arterioles or in the third-trimester myometrium. Furthermore, stellate transformation of EVTs precedes its interactions with the decidual arteriole. These specialized stellate trophoblasts invade and infiltrate the tunica media, accompanying lacuna formation inside the vessel wall and perturbation of actin fibre alignment of the tunica media. CONCLUSION: Stellate transformation of trophoblasts may explain controlled invasion of EVTs and probably plays a key role in initiating cell-cell interaction in decidual vascular remodelling.

Genetic screening of karyotypes and azoospermic factors for infertile men who are candidates for ICSI.

The overall incidence of chromosomal abnormalities was 8%. There was no single distinctive feature of semen parameters predictive of the existence of a chromosomal anomaly. All of the patients with obstructive azoospermia had normal karyotypes and AZF. Three patients out of 13 (23%) with nonobstructive azoospermia without 47,XXY had AZF deletions, as well as two (5%) of 43 with severe oligozoospermia. Ninety-two couples underwent 112 ICSI cycles for which a pregnancy rate of 58% was achieved. Five patients with abnormal karyotypes underwent 6 cycles of ICSI that resulted in 1 successful pregnancy. Two patients with AZF deletions achieved pregnancies. One ICSI-derived male had the same AZF deletion as his father, and 1 female baby had no risk of AZF deletion. The authors recommend karyotyping, excluding those with obstructive causes, prior to ICSI for genetic counseling.

Effects of cryopreservation on meiotic spindles of oocytes and its dynamics after thawing: clinical implications in oocyte freezing--a review article.

Embryo freezing has been a successful practice, but oocyte cryopreservation formerly achieved poorer results. This was mainly due to low rates of survival, fertilization, and development. The major dissimilarities for oocytes to embryos are the character of the plasma membrane, the presence of cortical granules, at the metaphase of meiosis II with the spindle system. In addition, the oocytes must be fertilized by sperm at the appropriate time. To improve the survival rate, a refined slow freezing method with increased sucrose concentration would dehydrate oocytes more sufficiently. Vitrification is another approach to prevent ice crystal formation. Intracytoplasmic sperm injection is used to overcome possible zona hardening from the release of cortical granules. The microtubules of meiotic spindles are vulnerable to the thermal changes and would depolymerize. Cryopreserved oocytes exhibited serious disturbances of the microtubules immediately after thawing. Fertilization of oocytes with disorganized spindles could lead to chromosomal aneuploidy, digyny, and arrest of cleavage. After incubation, the microtubules would repolymerize in a time-dependent way. Normal fertilization and development of cryopreserved oocytes improved after appropriate incubation and timing of insemination, compatible with recovery of the spindles. With the improvement of survival, fertilization, and cleavage, oocyte cryopreservation would gain an imperative role.

Effects of fertilization promoting peptide, adenosine, and pentoxifylline on thawed human sperm.

Fertilization promoting peptide (FPP) and adenosine were demonstrated to be potential modulators of sperm capacitation in mammals. Both FPP and adenosine, by modulating the adenylate cyclase (AC)/cAMP signaling pathway, elicit similar biphasic responses in mammalian sperm (i.e., stimulating capacitation and inhibiting spontaneous acrosome loss). Pentoxifylline, an artificial sperm stimulant, is clinically used to enhance motility of sperm from infertile men. By inhibiting phosphodiesterase, pentoxifylline increases the intracellular cAMP level of sperm, and thus contributes to capacitation, hyperactivation, and acrosome reaction in animal studies. The effects of FPP, adenosine, and pentoxifylline on thawed human sperm are stressed. Chlortetracycline (CTC) fluorescence assessment revealed that none of the 3 reagents improved fertilization ability of post-thawed sperm. Motility studies with computer-aided sperm analyzer (CASA) showed significantly smaller STR (straight-line velocity) and LIN (linearity) in the FPP-treated group at 4 h of incubation p

Effectiveness of postoperative adjuvant therapy in improving reproductive outcome of endometriosis-associated infertility.

BACKGROUND AND PURPOSE: Treatment of endometriosis-associated infertility has not yet become standardized. Various protocols including surgical treatment, medical therapy, and a combination of both have been suggested but their use remains controversial. The objective of the present study was to determine whether postoperative adjuvant therapy for endometriosis is effective in improving reproductive outcome. METHODS: Medical records of infertile patients with newly diagnosed endometriosis treated in a university teaching hospital during a 50-month period were reviewed. After exclusion of patients with other major infertility factors, a total of 209 patients were included in the retrospective analysis. These patients were divided into those receiving (n = 78) or not receiving (n = 131) peri- or postoperative adjuvant medical therapy. The adjuvant therapies included danazol (n = 62), gonadotropin releasing hormone analogues (n = 11), progestins (n = 3), oral contraceptives (n = 1), and mixed treatment (n = 1). RESULTS: The pregnancy rate was lower in those receiving adjuvant therapy, although this result was not significant (32.1% vs 45.8%; p = 0.05). When patients using postoperative danazol therapy were considered alone, the pregnancy rate in patients receiving adjuvant therapy was significantly lower than that in patients not receiving it (p = 0.047). When the stage of endometriosis was considered, the pregnancy rate in patients receiving adjuvant therapy was again lower than in those not receiving it in patients with minimal or mild endometriosis (42.9% vs 60%; p = 0.043). However, in patients with moderate or severe endometriosis, the pregnancy rate was not different in the two groups (31% vs 36%; p = 0.56). Postoperative assisted reproductive techniques (ART) including controlled ovarian hyperstimulation/intrauterine insemination (COH/IUI) and in vitro fertilization (IVF) were effective in improving the pregnancy rates for all patients (53.9% with ART vs 33.1% without; p = 0.003) and for patients with advanced endometriosis (47.7% with ART vs 27.2% without; p = 0.016). CONCLUSIONS: Our results suggest that postoperative adjuvant therapy is ineffective in improving reproductive outcome in patients with either early (minimal or mild) or advanced (moderate and severe) endometriosis. This finding suggests that if fertility is the goal of treatment, adjuvant therapy may be unnecessary after surgery. In contrast, our data suggest that empirical ART, including COH/IUI or IVF, may be a better alternative to improve the pregnancy outcome after surgery.

Vitrification of mouse oocytes using closed pulled straws (CPS) achieves a high survival and preserves good patterns of meiotic spindles, compared with conventional straws, open pulled straws (OPS) and grids.

BACKGROUND: We modified the loading of pulled straws into a new closed system, called closed pulled straws (CPS) for holding oocytes for vitrification. The morphological survival, dynamics of meiotic spindles, and fertilization in vitro of vitrified oocytes using CPS were compared with conventional straws, open pulled straws (OPS), and grids. METHODS: Surviving oocytes were stained for spindles and chromosomes after 1, 2 and 3 h incubations, and compared with controls. The capacity of fertilization and embryonic cleavage were examined in vitro. RESULTS: The survival rates of the CPS (79%) and straw (77%) groups were significantly higher (P < 0.05) than the OPS (63%) and grid (39%) groups. At a 1h incubation, vitrified oocytes of four groups had significantly fewer normal spindles than controls (P < 0.05). The straw group was inferior to the others in spindle morphology (P < 0.05). After a 3 h incubation, recovery of vitrified oocytes with normal spindles was significantly improved in all groups (P < 0.05). The percentages of fertilization and blastocyst formation of vitrified oocytes after a 1 h incubation was significantly lower than controls (P < 0.05), but they were improved after 2 or 3 h incubations (P < 0.05). CONCLUSIONS: Oocytes vitrified using CPS, OPS or grids could lessen spindle injuries and expedite recuperation. The survival using OPS or grids is lower. Sufficient culture time for recovery of meiotic spindle would be imperative for fertilization events of vitrified oocytes. CPS has the advantages of achieving a high survival and preserving good spindles.

Distribution of Th1 and Th2 cell populations in human peripheral and decidual T cells from normal and anembryonic pregnancies.

OBJECTIVE: To examine whether maternal immune responses during normal pregnancy are Th2 biased and whether there are specific changes when anembryonic pregnancy occurs. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology at a university hospital. PATIENT(S): We studied 32 pregnant women receiving elective abortions of normal pregnancies and 35 women with anembryonic pregnancies between 6 weeks and 10 weeks of gestational age. INTERVENTION(S): Using the multilabeling capability of three-color flow cytometry, it is possible to measure intracellular cytokines and cell surface markers simultaneously to determine which cells are the cytokine-producing cells. MAIN OUTCOME MEASURE(S): We examined the extent and proportion of mononuclear cells expressing specific T-cell surface markers and cytokines, interferon gamma, and interleukin 4 in the peripheral blood and deciduae. Secreted cytokines in the supernatants after 24-hour culture were also compared. RESULT(S): During the unstimulated status, the proportion of IL-4-secreting cells significantly exceeded that of IFN-gamma-secreting cells in the peripheral blood and decidua in normal pregnancies and was significantly decreased when anembryonic pregnancies occurred. Consequently, the Th1/Th2 ratios were increased during anembryonic pregnancies. However, after 24-hour culture, only another Th2-type cytokine, IL-10, was markedly increased and exceeded IFN-gamma secretion in cultures from both the peripheral blood and decidua in normal pregnancies. CONCLUSION(S): The decidual T lymphocytes are Th2 predominant. When anembryonic pregnancy occurs, this Th2 predominance disappears.

Maternal serum C-reactive protein level does not change significantly after fetal reduction: it could be used as an indicator of chorioamnionitis.

PURPOSE: This study was aimed at investigating the diagnostic value of maternal serum C-reactive protein (CRP) in the recognition of chorioamnionitis in patients undergoing fetal reduction. METHODS: Seventy-one gravidas with high-order multifetal pregnancies, including 46 with triplets, 18 with quadruplets, and 7 with quintuplets, who underwent transabdominal fetal reduction to twins during the 10th-14th gestational week were recruited. The subjects were followed up clinically and ultrasonographically 1 week and 1 month after fetal reduction for signs of infection, premature uterine contraction, and premature rupture of the membranes CRP levels were measured prior to fetal reduction and at follow-up examinations, and were compared. RESULTS: Among the 71 mothers, 65 (92%) were normal after fetal reduction. The CRP levels were not significantly different prior to the procedure (0.27 +/- 0.26 mg/dL), and 1 week (0.23 +/- 0.24 mg/dL) and 1 month (0.24 +/- 0.20 mg/dL) later. There was no correlation between the number of fetuses reduced and the CRP levels. Six (8%) experienced leakage of amniotic fluid after fetal reduction. Three patients had normal CRP levels at that time and at the following tests. The pregnancies continued smoothly after conservative treatment. The other three patients had elevated CRP levels when leakage of amniotic fluid occurred. Fever and uterine irritability developed subsequently despite parenteral antibiotics and tocolytic therapy. Daily checks showed increasing CRP levels. The pregnancies were aborted, and the histology of the placental membranes revealed chorioamnionitis with infiltration of acute inflammatory cells. CONCLUSIONS: The absorption of inactive gestational tissue after fetal reduction did not affect CRP levels. CRP may be used as a marker of intrauterine infection after fetal reduction.

Predominant Th2/Tc2 polarity of tumor-infiltrating lymphocytes in human cervical cancer.

Cytotoxic T lymphocytes (Tc) play a central role in cellular immunity against cancers. The cytotoxic potential of freshly isolated tumor-infiltrating lymphocytes (TILs) is usually not expressed. This suggests the possible existence of as yet unspecified and perhaps complex immunosuppressive factors or cytokines that affect the anti-tumor capacity of these TILs in the tumor milieu. In the present study, we demonstrated for the first time that TILs derived from human cervical cancer tissue consist mainly of Th2/Tc2 phenotypes. In vitro kinetic assays further revealed that cancer cells could direct the tumor-encountered T cells toward the Th2/Tc2 polarity. Cancer cells promote the production of IL-4 and down-regulate the production of IFN-gamma in cancer-encountered T cells. The regulatory effects of cervical cancer cells are mediated mainly by IL-10, and TGF-beta plays only a synergistic role. The cancer-derived effects can be reversed by neutralizing anti-IL-10 and anti-TGF-beta Abs. IL-10 and TGF-beta are present in cancer tissue and weakly expressed in precancerous tissue, but not in normal cervical epithelial cells. Our study strongly suggests important regulatory roles of IL-10 and TGF-beta in cancer-mediated immunosuppression.

Elevated E2: oocyte ratio in women undergoing IVF and tubal ET. Correlation with a decrease in the implantation rate.

OBJECTIVE: To investigate the influence of various estradiol (E2): oocyte ratios on reproductive outcome in women undergoing in vitro fertilization and tubal embryo transfer (IVF-TET). STUDY DESIGN: Two hundred seven women undergoing 251 IVF-TET cycles were recruited in this retrospective study. All the women received a flare-up gonadotropin releasing hormone agonist (GnRHa) protocol to achieve ovarian hyperstimulation. Oocyte retrieval was performed 34-36 hours after human chorionic gonadotropin (hCG) injection, followed by TET two days later. RESULTS: An E2: oocyte ratio > or = 350 pg/mL had a higher E2 level (2,213 +/- 2,258 vs. 1,553 +/- 972 pg/mL, P < .05) and fertilization rate (77 +/- 23 vs. 64 +/- 23%, P < .001) but a lower oocyte number (4.8 +/- 4.7 vs. 7.6 +/- 4.8, P < .001) than in those with a ratio < 350 pg/mL. The pregnancy (17.9% vs. 32.8%, P = .03) and implantation (5.3% vs. 12.9%, P = .008) rates were significantly decreased in cycles with an E2: oocyte ratio > or = 350 pg/mL as compared to those with a ratio < 350 pg/mL. CONCLUSION: IVF-TET cycles with an elevated E2: oocyte ratio correlated with lower pregnancy and implantation rates. The poor reproductive outcome possibly was due to the relatively high E2 concentration, which might have a detrimental effect on endometrial receptivity.

Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia.

OBJECTIVE: Maternal serum placenta growth factor levels have been shown to be significantly reduced in women with established preeclampsia. However, the temporal change in serum placenta growth factor levels before the clinical onset of preeclampsia is not known. STUDY DESIGN: Serum samples were collected from patients at the first prenatal (5-15 weeks' gestation), second-trimester (16-20 weeks' gestation), and third-trimester (26-30 weeks' gestation) visits. Serum placenta growth factor levels were determined and analyzed according to pregnancy outcome. RESULTS: Maternal placenta growth factor levels during normal gestation increased dramatically from the first to the third trimester. At the same gestational time points, in contrast, significantly lower serum placenta growth factor levels were found in patients in whom mild or severe preeclampsia eventually developed (P <.01). Low maternal serum placenta growth factor levels during early gestation were associated with a significant odds ratio for development of preeclampsia (P <.005). CONCLUSION: Relatively decreased levels of serum placenta growth factor occur before the onset of clinical preeclampsia, which suggests that placenta growth factor measurement could be used to discriminate those pregnancies predisposed to development of preeclampsia.

Mouse embryo toxicity of IL-6 in peritoneal fluids from women with or without endometriosis.

BACKGROUND: To determine whether there is a factor (or factors) in the peritoneal fluid of endometriosis patients that impairs embryo growth and embryo implantation. METHODS: Growth and development of two-cell mouse embryos which were cultured in media with peritoneal fluid from women with or without endometriosis and interleukin-1-beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels in conditioned media were measured. RESULTS: The blastocyst rate in the non-endometriosis group was 46.4 +/- 31.1%, and that of the endometriosis group was 54.6 +/- 28.7%. Logistic regression analysis using the criteria of blastocyst development in 454 embryos, showed that the peritoneal fluid from endometriosis could promote (p=0.015) but IL-6 could arrest embryo growth to blastocyst (p=0.025). IL-1beta and TNF-alpha levels had no significant effect on blastocyst formation. CONCLUSION: Peritoneal fluid from women with endometriosis was not toxic to mouse embryo development. However, IL-6 in the peritoneal fluid deteriorated the growth and development of mouse embryos.

A novel role of metalloproteinase in cancer-mediated immunosuppression.

Depressed immune responses have been observed frequently in cancer patients. In a variety of human malignancies, the expression of interleukin-2 receptor alpha (IL-2R alpha) on activated tumor-infiltrating lymphocytes was down-regulated. Because IL-2R alpha plays a pivotal role in the development and propagation of functional T cells, its depressed expression may result in poor function of tumor-reactive cytotoxic lymphocytes. For elucidating the mechanism responsible for down-regulation of IL-2R alpha, a coculture model of in vitro mixed autologous lymphocytes and tumor cells was established. Kinetic analysis showed that cervical cancer cells down-regulated IL-2R alpha expression on encountered T cells. The amount of IL-2R alpha mRNA in tumor-infiltrating lymphocytes-derived CD8+ T cells was compatible with that in the corresponding activated CD8+ T cells. Additional evidence showed that cervical cancer cells could induce the release of soluble IL-2R alpha expression on encountered T cells. By using protease inhibition assays we demonstrated that tissue inhibitors of metalloproteinase abrogated the cancer-mediated IL-2R alpha proteolytic process and restored the T-cell proliferation function. Immunohistochemical stainings further revealed prominent metalloproteinase (MMP) expressions, including MMP-1, MMP-2, and MMP-9, in cervical cancer tissues. Additional in vitro studies showed that MMP-9 mediates cleavage of IL-2R alpha and down-regulates the proliferative capability of cancer-encountered T cells. Our findings suggest a new role of MMPs in tumor-mediated immunosuppression and provide a possible therapeutic potential for patients with cervical cancer.

Increase in the production of interleukin-10 early after implantation is related to the success of pregnancy.

PROBLEM: To study the correlation of interleukin (IL)-10, IL-11 leukemia inhibitory factor (LIF), placental growth factor (PIGF), and transforming growth factor (TGF)-beta and outcome of human pregnancy. METHOD OF STUDY: We prospectively measured the serum levels of these cytokines in patients undergoing in vitro fertilization (IVF) programs. A total of 60 women (non-pregnant, n = 27; early abortions, n = 12; normal pregnancies, n = 21) were enrolled. RESULTS: There was no difference in the cytokines studied on D0 and D14 among the three groups of women. The increase in PIGF from D0 to D14 after human chorionic gonadotropin (hCG) injection was greater in pregnant women than in non-pregnant women; however, the difference did not reach significance (P = 0.068). The increase in IL-10 production from D14 to D21 was significant in women with successful pregnancies compared to women in the abortion group. CONCLUSIONS: This increase in IL-10 may be important in sustaining a normal pregnancy early after implantation.