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Autophagy is one of the underlying causes of resistance to many antitumor drugs, including cisplatin (DDP). The low-density lipoprotein receptor (LDLR) is a regulator of ovarian cancer (OC) progression. However, whether LDLR regulates DDP resistance in OC via autophagy-related pathways remains unclear. LDLR expression was measured by quantitative real-time PCR, western blot (WB) and IHC staining. A Cell Counting Kit 8 assay was employed to evaluate DDP resistance and cell viability, and flow cytometry was used to assess apoptosis. WB analysis was employed to evaluate the expression of autophagy-related proteins and PI3K/AKT/mTOR signaling pathway proteins. The autophagolysosomes and the fluorescence intensity of LC3 were observed by transmission electron microscopy and immunofluorescence staining, respectively. A xenograft tumor model was established to explore the role of LDLR in vivo. LDLR was highly expressed in OC cells, which was correlated with disease progression. In DDP-resistant OC cells, high LDLR expression was related to DDP resistance and autophagy. Downregulation of LDLR repressed autophagy and growth in DDP-resistant OC cell lines by activating the PI3K/AKT/mTOR pathway, and these effects were eliminated by an mTOR inhibitor. In addition, LDLR knockdown also reduced OC tumor growth by suppressing autophagy associated with the PI3K/AKT/mTOR pathway. LDLR promoted autophagy-mediated DDP resistance in OC associated with the PI3K/AKT/mTOR pathway, indicating that LDLR might be a new target to prevent DDP resistance in OC patients., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background: Several studies have reported the prognostic value of ultrasound elastography (UE) in patients receiving neoadjuvant chemotherapy (NACT) for breast cancer. However, the assessment of parameters differed between shear-wave elastography and strain elastography in terms of measured elasticity parameter and mode of imaging. It is important, therefore, to assess the accuracy of the two modes of elastography., Aim: To assess the accuracy of UE for predicting the pathologic complete response (pCR) in breast cancer patients following NACT., Methods: A comprehensive and systematic search was performed in the databases of MEDLINE, EMBASE, SCOPUS, PubMed Central, CINAHL, Web of Science and Cochrane library from inception until December 2020. Meta-analysis was performed using STATA software "Midas" package., Results: A total of 14 studies with 989 patients were included. The pooled sensitivities were 86% [95% confidence interval (CI): 76%-92%] for UE, 77% (95%CI: 68%-84%) for shear-wave elastography, and 92% (95%CI: 73%-98%) for strain-wave elastography. The pooled score specificities were 86% (95%CI: 80%-90%) for UE, 84% (95%CI: 72%-91%) for shear-wave elasticity, and 87% (95%CI: 81%-92%) for strain-wave elastography. A significant heterogeneity was found among studies based on the chi-square test results and an I 2 statistic > 75%., Conclusion: Strain-wave type of UE can accurately predict the pCR following NACT amongst breast cancer patients. Studies exploring its accuracy in different ethnic populations are required to strengthen the evidence., Competing Interests: Conflict-of-interest statement: The authors deny any conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Curing HIV infection has been thwarted by the persistent reservoir of latently infected CD4 + T cells, which reinitiate systemic infection after antiretroviral therapy (ART) interruption. To evaluate reservoir depletion strategies, we developed a novel preclinical in vivo model consisting of immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells (PBMC) from long-term ART-suppressed HIV-infected donors. In the absence of ART, these mice developed rebound viremia which, 2 weeks after PBMC injection, was 1,000-fold higher (mean = 9,229,281 HIV copies/ml) in mice injected intrasplenically than in mice injected intraperitoneally (mean = 6,838 HIV copies/ml) or intravenously (mean = 591 HIV copies/ml). One week after intrasplenic PBMC injection, in situ hybridization of the spleen demonstrated extensive disseminated HIV infection, likely initiated from in vivo -reactivated primary latently infected cells. The time to viremia was delayed significantly by treatment with a broadly neutralizing antibody, 10-1074, compared to treatment with 10-1074-FcR null , suggesting that 10-1074 mobilized Fc-mediated effector mechanisms to deplete the replication-competent reservoir. This was supported by phylogenetic analysis of Env sequences from viral-outgrowth cultures and untreated, 10-1074-treated, or 10-1074-FcR null -treated mice. The predominant sequence cluster detected in viral-outgrowth cultures and untreated mouse plasma was significantly reduced in the plasma of 10-1074-treated mice, whereas two new clusters emerged that were not detected in viral-outgrowth cultures or plasma from untreated mice. These new clusters lacked mutations associated with 10-1074 resistance. Taken together, these data indicated that 10-1074 treatment depletes the reservoir of latently infected cells harboring replication competent HIV. Furthermore, this mouse model represents a new in vivo approach for the preclinical evaluation of new HIV cure strategies. IMPORTANCE Sustained remission of HIV infection is prevented by a persistent reservoir of latently infected cells capable of reinitiating systemic infection and viremia. To evaluate strategies to reactivate and deplete this reservoir, we developed and characterized a new humanized mouse model consisting of highly immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells from long-term ART-suppressed HIV-infected donors. Reactivation and dissemination of HIV infection was visualized in the mouse spleens in parallel with the onset of viremia. The applicability of this model for evaluating reservoir depletion treatments was demonstrated by establishing, through delayed time to viremia and phylogenetic analysis of plasma virus, that treatment of these humanized mice with a broadly neutralizing antibody, 10-1074, depleted the patient-derived population of latently infected cells. This mouse model represents a new in vivo approach for the preclinical evaluation of new HIV cure strategies., (Copyright © 2019 American Society for Microbiology.)

Background: The Food and Drug Administration recently announced that the use of morcellation may cause fibroids or pelvic dissemination and metastasis of uterine sarcoma; therefore, the use of morcellation is limited in the USA. A large sample study is necessary to assess the proportion of uterine malignant tumors found in patients with laparoscopic myomectomy., Methods: A national multicenter study was performed in China. From 2002 to 2014, 33,723 cases were retrospectively selected. We calculated the prevalence and recorded the clinical characteristics of the patients with malignancy after morcellation application. A total of 62 cases were finally pathologically confirmed as malignant postoperatively. Additionally, the medical records of the 62 patients were analyzed in details., Results: The proportion of postoperative malignancy after morcellation application was 0.18% (62/33,723) for patients who underwent laparoscopic myomectomy. Nearly 62.9% (39/62) of patients had demonstrated blood flow signals in the uterine fibroids before surgery. And, 23 (37.1%) patients showed rapid growth at the final preoperative ultrasound. With respect to the pathological types, 38 (61.3%) patients had detectable endometrial stromal sarcoma, 13 (21.0%) had detectable uterine leiomyosarcoma, only 3 (3.2%) had detectable carcinosarcoma, and 5 (8.1%) patients with leiomyoma had an undetermined malignant potential., Conclusions: The proportion of malignancy is low after using morcellation in patients who undergo laparoscopic myomectomy. Patients with fast-growing uterine fibroids and abnormal ultrasonic tumor blood flow should be considered for malignant potential, and morcellation should be avoided.

Antibodies bound to human immunodeficiency virus type 1 (HIV-1) envelope protein expressed by infected cells mobilize antibody-dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to a functional HIV-1 cure. The most effective antibodies for controlling and eradicating HIV-1 infection would likely have the dual capacities of potently neutralizing a broad range of HIV-1 isolates and effectively mobilizing HIV-1-specific ADCC to eliminate HIV-1-infected cells. For this purpose, we constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and simian-human immunodeficiency virus (SHIV) infection in humanized mouse and macaque models, respectively, including in vivo neutralization of HIV-1 strains resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. We developed a novel humanized mouse model to evaluate in vivo human NK cell-mediated elimination of HIV-1-infected cells by ADCC and utilized it to demonstrate that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir. IMPORTANCE Mobilization of antibody-dependent cellular cytotoxicity (ADCC) to eliminate reactivated latent HIV-1-infected cells is a strategy which may contribute to depleting the HIV-1 reservoir and achieving a functional HIV-1 cure. To more effectively mobilize ADCC, we designed and constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and SHIV infection in humanized mouse and macaque models, respectively, including in vivo neutralization of an HIV-1 strain resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. Using a novel humanized mouse model, we demonstrated that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir., (Copyright © 2017 American Society for Microbiology.)

Functional analysis of T-cell responses in HIV-infected individuals has indicated that virus-specific CD8 + T cells with superior antiviral efficacy are well represented in HIV-1 controllers but are rare or absent in HIV-1 progressors. To define the role of individual T-cell receptor (TCR) clonotypes in differential antiviral CD8 + T-cell function, we performed detailed functional and mass cytometric cluster analysis of multiple CD8 + T-cell clones recognizing the identical HLA-B*2705-restricted HIV-1 epitope KK10 (KRWIILGLNK). Effective and ineffective CD8 + T-cell clones segregated based on responses to HIV-1-infected and peptide-loaded target cells. Following cognate peptide stimulation, effective HIV-specific clones displayed significantly more rapid TCR signal propagation, more efficient initial lytic granule release, and more sustained nonlytic cytokine and chemokine secretion than ineffective clones. To evaluate the TCR clonotype contribution to CD8 + T-cell function, we cloned the TCR α and β chain genes from one effective and two ineffective CD8 + T-cell clones from an elite controller into TCR-expressing lentivectors. We show that Jurkat/MA cells and primary CD8 + T cells transduced with lentivirus expressing TCR from one of the ineffective clones exhibited a level of activation by cognate peptide and inhibition of in vitro HIV-1 infection, respectively, that were comparable to those of the effective clonotype. Taken together, these data suggest that the potent antiviral capacity of some HIV-specific CD8 + T cells is a consequence of factors in addition to TCR sequence that modulate functionality and contribute to the increased antiviral capacity of HIV-specific CD8 + T cells in elite controllers to inhibit HIV infection. IMPORTANCE The greater ex vivo antiviral inhibitory activity of CD8 + T cells from elite controllers than from HIV-1 progressors supports the crucial role of effective HIV-specific CD8 + T cells in controlling HIV-1 replication. The contribution of TCR clonotype to inhibitory potency was investigated by delineating the responsiveness of effective and ineffective CD8 + T-cell clones recognizing the identical HLA-B*2705-restricted HIV-1 Gag-derived peptide, KK10 (KRWIILGLNK). KK10-stimulated "effective" CD8 + T-cell clones displayed significantly more rapid TCR signal propagation, more efficient initial lytic granule release, and more sustained cytokine and chemokine secretion than "ineffective" CD8 + T-cell clones. However, TCRs cloned from an effective and one of two ineffective clones conferred upon primary CD8 + T cells the equivalent potent capacity to inhibit HIV-1 infection. Taken together, these data suggest that other factors aside from intrinsic TCR-peptide-major histocompatibility complex (TCR-peptide-MHC) reactivity can contribute to the potent antiviral capacity of some HIV-specific CD8 + T-cell clones., (Copyright © 2017 American Society for Microbiology.)

Mice cannot be used as a model to evaluate HIV-1 therapeutics because they do not become infected by HIV-1 due to structural differences between several human and mouse proteins required for HIV-1 replication. This has limited their use for in vivo assessment of anti-HIV-1 therapeutics and the mechanism by which cofactors, such as illicit drug use accelerate HIV-1 replication and disease course in substance abusers. Here, we describe the development and application of two in vivo humanized mouse models that are highly sensitive and useful models for the in vivo evaluation of candidate anti-HIV therapeutics. The first model, hu-spl-PBMC-NSG mice, uses NOD-SCID IL2rγ(-/-) (NSG) mice intrasplenically injected with human peripheral blood mononuclear cells (PBMC) which develop productive splenic HIV-1 infection after intrasplenic inoculation with a replication-competent HIV-1 expressing Renilla reniformis luciferase (HIV-LucR) and enables investigators to use bioluminescence to visualize and quantitate the temporal effects of therapeutics on HIV-1 infection. The second model, hCD4/R5/cT1 mice, consists of transgenic mice carrying human CD4, CCR5 and cyclin T1 genes, which enables murine CD4-expressing cells to support HIV-1 entry, Tat-mediated LTR transcription and consequently develop productive infection. The hCD4/R5/cT1 mice develop disseminated infection of tissues including the spleen, small intestine, lymph nodes and lungs after intravenous injection with HIV-1-LucR. Because these mice can be infected with HIV-LucR expressing transmitted/founder and clade A/E and C Envs, these mouse models can also be used to evaluate the in vivo efficacy of broadly neutralizing antibodies and antibodies induced by candidate HIV-1 vaccines. Furthermore, because hCD4/R5/cT1 mice can be infected by vaginal inoculation with replication-competent HIV-1 expressing NanoLuc (HIV-nLucR)-, this mouse model can be used to evaluate the mechanisms by which substance abuse and other factors enhance mucosal transmission of HIV-1.

Unlabelled: Epidemiological studies have demonstrated that herpes simplex virus 2 (HSV-2) infection significantly increases the risk of HIV-1 acquisition, thereby contributing to the expanding HIV-1 epidemic. To investigate whether HSV-2 infection directly facilitates mucosal HIV-1 acquisition, we used our transgenic hCD4/R5/cT1 mouse model which circumvents major entry and transcription blocks preventing murine HIV-1 infection by targeting transgenic expression of human CD4, CCR5, and cyclin T1 genes to CD4(+) T cells and myeloid-committed cells. Productive infection of mucosal leukocytes, predominantly CD4(+) T cells, was detected in all hCD4/R5/cT1 mice intravaginally challenged with an HIV-1 infectious molecular clone, HIV-Du151.2env-NLuc, which expresses an env gene (C.Du151.2) cloned from an acute heterosexually infected woman and a NanoLuc luciferase reporter gene. Lower genital tract HIV-1 infection after HIV-Du151.2env-NLuc intravaginal challenge was increased ~4-fold in hCD4/R5/cT1 mice coinfected with HSV-2. Furthermore, HIV-1 dissemination to draining lymph nodes was detected only in HSV-2-coinfected mice. HSV-2 infection stimulated local infiltration and activation of CD4(+) T cells and dendritic cells, likely contributing to the enhanced HIV-1 infection and dissemination in HSV-2-coinfected mice. We then used this model to demonstrate that a novel gel containing tenofovir disoproxil fumarate (TDF), the more potent prodrug of tenofovir (TFV), but not the TFV microbicide gel utilized in the recent CAPRISA 004, VOICE (Vaginal and Oral Interventions to Control the Epidemic), and FACTS 001 clinical trials, was effective as preexposure prophylaxis (PrEP) to completely prevent vaginal HIV-1 infection in almost half of HSV-2-coinfected mice. These results also support utilization of hCD4/R5/cT1 mice as a highly reproducible immunocompetent preclinical model to evaluate HIV-1 acquisition across the female genital tract., Importance: Multiple epidemiological studies have reported that genital herpes simplex virus 2 (HSV-2) infection increases the risk of HIV-1 sexual acquisition by severalfold. Understanding the underlying mechanisms by which HSV-2 facilitates HIV-1 infection and optimizing the efficacy of therapies to inhibit HIV-1 infection during HSV-2 coinfection should contribute to reducing HIV-1 transmission. Using our novel transgenic hCD4/R5/cT1 mouse model infectible with HIV-1, we demonstrated that HSV-2 infection enhances vaginal transmission and dissemination of HIV-1 infection while stimulating recruitment and activation of CD4(+) T cells and dendritic cells in the lower genital tract. HIV acquisition by hCD4/R5/cT1 mice vaginally coinfected with HSV-2 could be completely prevented in almost half the mice by preexposure prophylaxis (PrEP) with a novel gel containing tenofovir disoproxil fumarate (TDF), the tenofovir prodrug, but not with the tenofovir microbicide gel utilized in CAPRISA-004, VOICE, and FACTS-001 clinical trials. The hCD4/R5/cT1 mice represent a new preclinical mouse model to evaluate vaginal HIV-1 acquisition., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

MicroRNAs play critical roles in regulating tumor occurrence and drug sensitivity in ovarian cancers. This study aimed to investigate the key members of MicroRNAs (miRNAs) involved in modulating tumor initiation and drug resistance in primary ovarian cancer cells. An in vitro assay based on tumor clonal formation was established to evaluate tumorigenicity and cisplatin sensitivity. By performing real-time polymerase chain reaction, we examined the expression of nine microRNAs associated with the pathology of ovarian cancers in primary ovarian tumor cells, which were surgically resected from 46 patients with distinct sensitivity to platinum-based chemotherapy. MiR-9, miR-145, and miR-429 were expressed significantly higher in drug-sensitive patients (n = 26) than in drug-resistant ones (n = 20), while higher miR-26a expression was found in resistant patients (p < 0.05). In addition, tumor cells from drug sensitive patients were more tumorigenic than those of drug resistance (p = 0.0013). Cisplatin treatment led to a sharp decrease of clonal formation of drug-sensitive cells but showed slight effects on drug resistant cells. Specific anti-miRs were then employed to downregulate the expression of microRNAs in primary tumor cells. Inhibition of miR-9 resulted in decreased clonal formation and sensitivity to cisplatin, while the knockdown of other three microRNAs did not show any influence in tumorigenesis and drug sensitivity. In conclusion, this study showed that in primary ovarian tumor cells, high expression of miR-9 was associated with enhanced tumorigenesis and increased sensitivity of the tumor cells to cisplatin treatment.

Unlabelled: Natural killer (NK) cells with anti-HIV-1 activity may inhibit HIV-1 replication and dissemination during acute HIV-1 infection. We hypothesized that the capacity of NK cells to suppress acute in vivo HIV-1 infection would be augmented by activating them via treatment with an interleukin-15 (IL-15) superagonist, IL-15 bound to soluble IL-15Rα, an approach that potentiates human NK cell-mediated killing of tumor cells. In vitro stimulation of human NK cells with a recombinant IL-15 superagonist significantly induced their expression of the cytotoxic effector molecules granzyme B and perforin; their degranulation upon exposure to K562 cells, as indicated by cell surface expression of CD107a; and their capacity to lyse K562 cells and HIV-1-infected T cells. The impact of IL-15 superagonist-induced activation of human NK cells on acute in vivo HIV-1 infection was investigated by using hu-spl-PBMC-NSG mice, NOD-SCID-IL2rγ(-/-) (NSG) mice intrasplenically injected with human peripheral blood mononuclear cells (PBMCs) which develop productive in vivo infection after intrasplenic inoculation with HIV-1. IL-15 superagonist treatment potently inhibited acute HIV-1 infection in hu-spl-PBMC-NSG mice even when delayed until 3 days after intrasplenic HIV-1 inoculation. Removal of NK cells from human PBMCs prior to intrasplenic injection into NSG mice completely abrogated IL-15 superagonist-mediated suppression of in vivo HIV-1 infection. Thus, the in vivo activation of NK cells, integral mediators of the innate immune response, by treatment with an IL-15 superagonist increases their anti-HIV activity and enables them to potently suppress acute in vivo HIV-1 infection. These results indicate that in vivo activation of NK cells may represent a new immunotherapeutic approach to suppress acute HIV-1 infection., Importance: Epidemiological studies have indicated that NK cells contribute to the control of HIV-1 infection, and in vitro studies have demonstrated that NK cells can selectively kill HIV-1-infected cells. We demonstrated that in vivo activation of NK cells by treatment with an IL-15 superagonist that potently stimulates the antitumor activity of NK cells markedly inhibited acute HIV-1 infection in humanized mice, even when activation of NK cells by IL-15 superagonist treatment is delayed until 3 days after HIV-1 inoculation. NK cell depletion from PBMCs prior to their intrasplenic injection abrogated the suppression of in vivo HIV-1 infection observed in humanized mice treated with the IL-15 superagonist, demonstrating that activated human NK cells were mediating IL-15 superagonist-induced inhibition of acute HIV-1 infection. Thus, in vivo immunostimulation of NK cells, a promising therapeutic approach for cancer therapy, may represent a new treatment modality for HIV-1-infected individuals, particularly in the earliest stages of infection., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Objective: To investigate the expression of platelet derived growth factor-BB (PDGF-BB) and microvessel density (MVD) marked with CD34 in clear cell renal cell carcinoma (CCRCC) and explore their relevance to clinicopathologic features and prognoses of patients., Methods: Expressions of PDGF-BB and CD34 in the tissue samples of 100 clear cell renal cell carcinomas were detected by immunohistochemical (IHC) SP staining. The microvessel density (MVD) was counted using Weidner's method. For PDGF-BB assessment, the staining intensity and the proportion of positive tumor cells were analyzed. Staining was considered immunoreactive when brown granules were identified in the cytoplasm or nuclei of tumor cells. Staining intensity and the proportion of positively stained tumor cells in lesions was scored for further analysis. Statistical analysis was performed using the software SPSS 18.0., Results: The MVD value marked by CD34 in the 100 cancer tissues was (105.49 ± 37.95) profiles/HPF. The median value of MVD in the entire cohort was used as the cut-off point for low MVD group (42 cases) and high MVD group (58 cases). The MVD of the low and high MVD groups was (75.12 ± 22.41) profiles/ HPF and (135.86 ± 22.91) profiles/HPF, respectively, with a statistically significant difference (P < 0.001). MVD was significantly correlated with the tumor T staging, histopathological grading and postoperative metastasis in CCRCC (P < 0.05, respectively). Among the 100 CCRCC cases, there were 38 cases with low PDGF-BB expression and 62 cases with high PDGF-BB expression, and the expression of PDGF-BB was significantly correlated with tumor diameter, T staging, histopathological grading and postoperative metastasis in the CCRCC (P < 0.05, respectively). Kaplan-Meier survival analysis showed that the cancer specific survival (CSS) in CCRCC patients with high expression of MVD and PDGF-BB was significantly better than that in the group with low MVD and low PDGF-BB expression (P < 0.001, respectively). Expression of PDGF-BB protein was positively associated with the MVD assessed by Spearman's correlation and factor analysis (r = 0.461, P < 0.001)., Conclusion: Significantly increased MVD and PDGF-BB expression detected in CCRCC patients indicate a better tumor grading and staging, and a longer survival time.

Background: We aimed to evaluate the association of preoperative plasma fibrinogen levels with the clinicopathological parameters, disease-free survival, and overall survival in patients with renal cell carcinoma., Methods: We retrospectively studied 286 patients with renal cell carcinoma who underwent radical nephrectomy from 2000 to 2003 at one center. The plasma fibrinogen was routinely determined before operation in all patients. The correlation of preoperative plasma fibrinogen levels with clinicopathological findings was evaluated by t-test or analysis of variance (ANOVA) methods. As well, univariate and multivariate analyses were used to determine the association between the preoperative level of plasma fibrinogen and survival duration., Results: An elevated level of plasma fibrinogen was positively related to the Fuhrman grade (P < 0.001), tumor size (P < 0.001), and T stage (P < 0.001), but it was negatively related to histologic type (P = 0.266). Univariate analysis showed that the Fuhrman grade, tumor size, T stage, hemoglobin, corrected calcium, lactate dehydrogenase, and plasma fibrinogen level were significantly correlated with disease-free survival (P < 0.001, P < 0.001, P < 0.001, P < 0.001, P = 0.001, P < 0.001, and P < 0.001, respectively) and overall survival (P < 0.001, P = 0.001, P < 0.001, P < 0.001, P = 0.002, P = 0.001, and P < 0.001). Multivariate analysis showed that the plasma fibrinogen level remained as an independent prognostic factor for disease-free survival (P = 0.021) and overall survival (P < 0.001)., Conclusions: A high preoperative plasma fibrinogen level is an independent predictor of distant metastasis and survival prognosis after radical nephrectomy in patients with renal cell carcinoma.

Mice cannot be used to evaluate HIV-1 therapeutics and vaccines because they are not infectible by HIV-1 due to structural differences between several human and mouse proteins required for HIV-1 entry and replication including CD4, CCR5 and cyclin T1. We overcame this limitation by constructing mice with CD4 enhancer/promoter-regulated human CD4, CCR5 and cyclin T1 genes integrated as tightly linked transgenes (hCD4/R5/cT1 mice) promoting their efficient co-transmission and enabling the murine CD4-expressing cells to support HIV-1 entry and Tat-mediated LTR transcription. All of the hCD4/R5/cT1 mice developed disseminated infection of tissues that included the spleen, small intestine, lymph nodes and lungs after intravenous injection with an HIV-1 infectious molecular clone (HIV-IMC) expressing Renilla reniformis luciferase (LucR). Furthermore, localized infection of cervical-vaginal mucosal leukocytes developed after intravaginal inoculation of hCD4/R5/cT1 mice with the LucR-expressing HIV-IMC. hCD4/R5/cT1 mice reproducibly developed in vivo infection after inoculation with LucR-expressing HIV-IMC which could be bioluminescently quantified and visualized with a high sensitivity and specificity which enabled them to be used to evaluate the efficacy of HIV-1 therapeutics. Treatment with highly active anti-retroviral therapy or one dose of VRC01, a broadly neutralizing anti-HIV-1 antibody, almost completed inhibited acute systemic HIV-1 infection of the hCD4/R5/cT1 mice. hCD4/R5/cT1 mice could also be used to evaluate the capacity of therapies delivered by gene therapy to inhibit in vivo HIV infection. VRC01 secreted in vivo by primary B cells transduced with a VRC01-encoding lentivirus transplanted into hCD4/R5/cT1 mice markedly inhibited infection after intravenous challenge with LucR-expressing HIV-IMC. The reproducible infection of CD4/R5/cT1 mice with LucR-expressing HIV-IMC after intravenous or mucosal inoculation combined with the availability of LucR-expressing HIV-IMC expressing transmitted/founder and clade A/E and C Envs will provide researchers with a highly accessible pre-clinical in vivo HIV-1-infection model to study HIV-1 acquisition, treatment, and prevention.

Objective: To investigate the operative treatment for first-treated patients with malignant ovarian germ cell tumors who need preservation of fertility., Methods: The clinical data of 105 patients who were treated with fertility-sparing surgery in 11 hospitals from 1992 to 2010 were collected to evaluate the outcomes of different primary surgical operative procedures. All 105 cases were performed the surgeries that preserved fertility and divided into three groups according to the surgical approaches, comprehensive staging surgery group: 47 cases (44.8%) received comprehensive staging surgeries that including the ipsilateral oophorectomy + omentectomy + retropertoneal lymph node dissection ± appendectomy + multiple biopsies;oophorectomy group:45 cases (42.9%)received ipsilateral oophorectomy ± biopsy of contralateral ovary ± omentectomy;tumor resection group:13 cases (12.4%) received enucleation of the mass with preservation of the ovary. Differences were compared among the three groups of patients in the surgery-related indicators, complications, fertility and prognosis., Results: (1) Surgery-related indicators:the average blood loss of the comprehensive staging surgery group, the oophorectomy group and the tumor resection group were 496, 104 and 253 ml, the mean operation time were 176, 114 and 122 minutes, respectively, and there were significant differences among three groups (P = 0.011, P = 0.000). (2) Complication:the surgical complication rates of the three groups were 17% (8/47), 0 and 1/13, with significant differences (P = 0.015). (3) Reproductive function status: the pregnancy rate and birth rate of the three groups were no significant differences (9/19 vs. 7/19 vs. 2/3, P = 0.515; 8/19 vs. 5/19 vs. 2/3, P = 0.636). (4) PROGNOSIS: the recurrence rate of the three groups were significant differences [13% (6/47) vs. 0 vs. 2/13, P = 0.013], but the death rate with no significant differences [6% (3/47) vs. 0 vs. 0, P = 0.129]; The five-year survival rate of three different groups were 89%, 100% and 100% (P > 0.05), while disease free survival rate were 85%, 100% and 83% (P < 0.05), respectively., Conclusions: Compared with comprehensive staging surgery, oophorectomy group have higher surgical security and satisfactory prognosis, considerable pregnancy rates and birth rate. The tumor resection security may be reliable, but the prognosis is poor.

Objective: The Notch signaling pathway plays an important role in the stem cell signaling network and contributes to tumorigenesis. However, the functions of Notch signaling in ovarian cancer stem cells (OCSCs) are not well understood. We aimed to investigate the effects of Notch blockade on self-renewal and stemness maintenance of OCSCs., Methods: Ovarian cancer stem-like cells were enriched from ovarian cancer cell lines in serum-free medium. A γ-secretase inhibitor, (DAPT), was used to block Notch signaling. MTT assays were performed to assess self-renewal and proliferation inhibition, flow cytometry was performed to analyze cell surface marker and immunofluorescence, Western Blot and Real-time RT-PCR assays were performed to detect Oct4 and Sox2 protein and mRNA expression of the Ovarian cancer stem-like cells treated with DAPT., Results: Notch blockade markedly inhibits self-renewal and proliferation of ovarian cancer stem-like cells, significantly downregulates the expression of OCSCs-specific surface markers, and reduces protein and mRNA expression of Oct4 and Sox2 in OCSC-like cells., Conclusion: Our results suggest that Notch signaling is not only critical for the self-renewal and proliferation of OCSCs, but also for the stemness maintenance of OCSCs. The γ-secretase inhibitor is a promising treatment targeting OCSCs.

The primary aim of this study is to evaluate the clinical significance of E-cadherin protein expression and the methylation status in CDH1 promoter in endometrial cancer. The expression of E-cadherin and methylation in its promoter region was analyzed, retrospectively, in 152 clinical tissue samples from patients with endometrial lesions. We found that the hypermethylation of CDH1 promoter, which caused low expression of E-cadherin in endometrial cancer, was associated with not only clinicopathological progress of endometrial cancer but also with the overall 5-year clinical survival rate. The findings provide the potential therapeutic and prognostic target molecule for patients with endomethrial cancer.

Due to the inherent immune evasion properties of the HIV envelope, broadly neutralizing HIV-specific antibodies capable of suppressing HIV infection are rarely produced by infected individuals. We examined the feasibility of utilizing genetic engineering to circumvent the restricted capacity of individuals to endogenously produce broadly neutralizing HIV-specific antibodies. We constructed a single lentiviral vector that encoded the heavy and light chains of 2G12, a broadly neutralizing anti-HIV human antibody, and that efficiently transduced and directed primary human B cells to secrete 2G12. To evaluate the capacity of this approach to provide protection from in vivo HIV infection, we used the humanized NOD/SCID/gamma(c)(null) mouse model, which becomes populated with human B cells, T cells, and macrophages after transplantation with human hematopoietic stem cells (hu-HSC) and develops in vivo infection after inoculation with HIV. The plasma of the irradiated NOD/SCID/gamma(c)(null) mice transplanted with hu-HSC transduced with the 2G12-encoding lentivirus contained 2G12 antibody, likely secreted by progeny human lymphoid and/or myeloid cells. After intraperitoneal inoculation with high-titer HIV-1(JR-CSF), mice engrafted with 2G12-transduced hu-HSC displayed marked inhibition of in vivo HIV infection as manifested by a profound 70-fold reduction in plasma HIV RNA levels and an almost 200-fold reduction in HIV-infected human cell numbers in mouse spleens, compared to control hu-HSC-transplanted NOD/SCID/gamma(c)(null) mice inoculated with equivalent high-titer HIV-1(JR-CSF). These results support the potential efficacy of this new gene therapy approach of using lentiviral vectors encoding a mixture of broadly neutralizing HIV antibodies for the treatment of HIV infection, particularly infection with multiple-drug-resistant isolates.

Objective: To investigate the effects of biological characters of the human ovarian cell line (OVCAR) by stable transfection short hairpin RNA into the target HMGA1 gene., Methods: Experiments were divided into two groups: transfected the OVCAR cells with pSilence4.1-CMV-Hs plasmid as group A, while transfected OVCAR cells with pSilence4.1-CMV-Hn plasmid as group B, in which stably transfected cells were gained by antibiotic screening. The comparative expressions of HMGA1 were detected by RT-PCR and western blot. Methyl thiazolyl tetrazolium (MTT) method was applied to measure cell proliferation and at the same time, the cell growth curve was also be mapped. Vitro invasion assay was used to observe the invasion ability of the cancer cells, and the tumor growth of the nude mice inoculated of tumor cells were compared with before and after transfection., Results: In group A, the expression level of mRNA and protein HMGA1 gene in OVCAR cells were remarkably reduced before and after the stable transfected with HMGA1 siRNA, in which the percents of mRNA expression were [(86.3 ± 2.7)% vs. (35.8 ± 3.1)%, P < 0.05], the expression of protein were [(68.6 ± 2.8)% vs. (22.3 ± 4.2)%, P < 0.05)]. The OVCAR cell growth in stable transfection status was more significantly decreased than that in non-transfection status (P < 0.05). In group B, there were no statistical difference in the expression of HMGA1 siRNA, protein and the cell growth between before and after transfection states (P > 0.05). The invasion cell numbers were reduced from before to after transfection state in group A [(53 ± 6) vs. (21 ± 6), P < 0.05], while there was no significant difference in group B [(51 ± 6) vs. (47 ± 8), P > 0.05]. After inoculated transfected cells into nude mice, it took (6.0 ± 0.9) days to grow the planed tumors in group A, which was much shorter than that (12.3 ± 3.9) days in group B (P < 0.05). After 5 weeks, the tumor weight and volume in group A was were significantly lower than those in group B [(0.8 ± 0.3) g vs. (2.1 ± 0.4) g, (205 ± 34) mm(3) vs. (987 ± 82) mm(3), all P < 0.05]., Conclusion: HMGA1 siRNA could remarkably reduce the expression of HMGA1 gene in ovarian cell and also inhabit the ovarian cell growth.

To delineate the mechanistic basis for the epidemiological association between methamphetamine use and accelerated progression to AIDS, we evaluated the direct in vitro and in vivo effects of methamphetamine on HIV-1 replication. Methamphetamine administration significantly increased HIV-1 production by both HIV-infected monocytes and CD4 T lymphocytes in vitro. In addition, in vivo methamphetamine treatment increased HIV production and viremia in mice transgenic for a replication-competent HIV provirus and human cyclin T1. Methamphetamine activated transcription of the HIV long terminal repeat (LTR) regulatory region, was associated with nuclear translocation of NF-kappaB. Our results provide further insights into the mechanisms by which methamphetamine accelerates disease course in HIV-infected individuals.

Background: Recent studies indicate that S100P expression may be a biomarker that can predict the success of cancer chemotherapy. Whether it is relevant to chemotherapeutics in ovarian cancer is unknown. In this study, we investigated the association of S100P expression with paclitaxel sensitivity in ovarian cancer cell lines., Methods: We measured S100P expression and paclitaxel resistance profiles in parent SKOV3 and OVCAR3 cell lines. Then, the two cell lines were transiently transfected with S100P siRNA. We also constructed an OVCAR3 cell clone that stably overexpressed S100P. The effect of S100P expression level on the survival of cells exposed to paclitaxel was measured using the MTT assay. S100P expression was evaluated by semi-quantitative RT-PCR and Western blotting. Significance of differences was calculated using independent samples t-test and one way analysis of variance (ANOVA)., Results: Lower S100P expression was associated with a survival advantage in OVCAR3 cells exposed to paclitaxel; the survival advantage in SKOV3 cells was smaller (P < 0.05). The survival advantage associated with decreased S100P expression was even greater for SKOV3 and OVCAR3 cells that had been transfected with S100P siRNA before being exposed to paclitaxel (P < 0.05). Consistent with this, the OVCAR3 cell clone that was transfected to overexpress S100P was more sensitive to paclitaxel (P < 0.05)., Conclusions: Low S100P expression contributes to drug resistance to paclitaxel in ovarian cancer cell lines. S100P expression thus might be a marker that can predict the effectiveness of paclitaxel based chemotherapy. Such a marker could be helpful in improving individual medication regimens for ovarian cancer patients.

In order to test the clinical capacity of hand-carried ultrasound (HCU) devices in elderly inpatients with heart disease, chamber sizes of heart structure, ventricular wall thickness and motion abnormality (WMA), mitral valve and tricuspid regurgitation evaluated by HCU devices in 401 elderly inpatients with heart disease were compared with those evaluated by comprehensive echocardiography (CE) devices. As a result, there was no significant difference in measurements of cardiac chamber dimensions or left ventricular ejection fraction between the two techniques. The HCU's WMA detection rate relative to the CE was 92.15%. Their conformable rates for detection of mitral and tricuspid regurgitation was 93% and 91.4% respectively. Therefore, we conclude that HCU is one of the practical modalities for diagnosis and monitoring in elderly inpatients with heart disease.

Inflammatory mediators and viral products produced by human immunodeficiency virus (HIV)-infected microglia and astrocytes perturb the function and viability of adjacent uninfected neuronal and glial cells and contribute to the pathogenesis of HIV-associated neurocognitive disorders (HAND). In vivo exposure to lipopolysaccharide (LPS) activates parenchymal microglia and astrocytes and induces cytokine and chemokine production in the brain. HIV-infected individuals display increased circulating LPS levels due to microbial translocation across a compromised mucosa barrier. We hypothesized that HIV-infected microglia and astrocytes display increased sensitivity to the proinflammatory effects of LPS, and this combines with the increased levels of systemic LPS in HIV-infected individuals to contribute to the development of HAND. To examine this possibility, we determined the in vivo responsiveness of HIV-infected microglia and astrocytes to LPS using our mouse model, JR-CSF/human cyclin T1 (JR-CSF/hu-cycT1) mice, which are transgenic for both an integrated full-length infectious HIV type 1 (HIV-1) provirus derived from the primary R5-tropic clinical isolate HIV-1(JR-CSF) regulated by the endogenous HIV-1 long terminal repeat and the hu-cycT1 gene under the control of a CD4 promoter. In the current report, we demonstrated that in vivo-administered LPS more potently activated JR-CSF/hu-cycT1 mouse microglia and astrocytes and induced a significantly higher degree of monocyte chemoattractant protein production by JR-CSF/hu-cycT1 astrocytes compared to that of the in vivo LPS response of control littermate mouse microglia and astrocytes. These results indicate that HIV infection increases the sensitivity of microglia and astrocytes to inflammatory stimulation and support the use of these mice as a model to investigate various aspects of the in vivo mechanism of HIV-induced neuronal dysfunction.

The human immunodeficiency virus type 1 (HIV-1)-specific CD8 cytotoxic T-lymphocyte (CTL) response plays a critical role in controlling HIV-1 replication. Augmenting this response should enhance control of HIV-1 replication and stabilize or improve the clinical course of the disease. Although cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection in immunocompromised patients can be treated by adoptive transfer of ex vivo-expanded CMV- or EBV-specific CTLs, adoptive transfer of ex vivo-expanded, autologous HIV-1-specific CTLs had minimal effects on HIV-1 replication, likely a consequence of the inherently compromised qualitative function of HIV-1-specific CTLs derived from HIV-1-infected individuals. We hypothesized that this limitation could be circumvented by using as an alternative source of HIV-1-specific CTLs, autologous peripheral CD8(+) T lymphocytes whose antigen specificity is redirected by transduction with lentiviral vectors encoding HIV-1-specific T-cell receptor (TCR) alpha and beta chains, an approach used successfully in cancer therapy. To efficiently convert peripheral CD8 lymphocytes into HIV-1-specific CTLs that potently suppress in vivo HIV-1 replication, we constructed lentiviral vectors encoding the HIV-1-specific TCR alpha and TCR beta chains cloned from a CTL clone specific for an HIV Gag epitope, SL9, as a single transcript linked with a self-cleaving peptide. We demonstrated that transduction with this lentiviral vector efficiently converted primary human CD8 lymphocytes into HIV-1-specific CTLs with potent in vitro and in vivo HIV-1-specific activity. Using lentiviral vectors encoding an HIV-1-specific TCR to transform peripheral CD8 lymphocytes into HIV-1-specific CTLs with defined specificities represents a new immunotherapeutic approach to augment the HIV-1-specific immunity of infected patients.

Human immunodeficiency virus type 1 (HIV-1)-encoded Tat provides transcriptional activation critical for efficient HIV-1 replication by interacting with cyclin T1 and recruiting P-TEFb to efficiently elongate the nascent HIV transcript. Tat-mediated transcriptional activation in mice is precluded by species-specific structural differences that prevent Tat interaction with mouse cyclin T1 and severely compromise HIV-1 replication in mouse cells. We investigated whether transgenic mice expressing human cyclin T1 under the control of a murine CD4 promoter/enhancer cassette that directs gene expression to CD4(+) T lymphocytes and monocytes/macrophages (hu-cycT1 mice) would display Tat responsiveness in their CD4-expressing mouse cells and selectively increase HIV-1 production in this cellular population, which is infected primarily in HIV-1-positive individuals. To this end, we crossed hu-cycT1 mice with JR-CSF transgenic mice carrying the full-length HIV-1(JR-CSF) provirus under the control of the endogenous HIV-1 long terminal repeat and demonstrated that human cyclin T1 expression is sufficient to support Tat-mediated transactivation in primary mouse CD4 T lymphocytes and monocytes/macrophages and increases in vitro and in vivo HIV-1 production by these stimulated cells. Increased HIV-1 production by CD4(+) T lymphocytes was paralleled with their specific depletion in the peripheral blood of the JR-CSF/hu-cycT1 mice, which increased over time. In addition, increased HIV-1 transgene expression due to human cyclin T1 expression was associated with increased lipopolysaccharide-stimulated monocyte chemoattractant protein 1 production by JR-CSF mouse monocytes/macrophages in vitro. Therefore, the JR-CSF/hu-cycT1 mice should provide an improved mouse system for investigating the pathogenesis of various aspects of HIV-1-mediated disease and the efficacies of therapeutic interventions.

The tissue culture of Saussurea involucrata (TCSauI) KAR. et KIR. was studied to determine its antiinflammatory and analgesic activities in experimental animals. Similar to wild S. involucrata, TCSauI at doses of 75-300 mg/kg i.g. for 7 d markedly inhibited hindpaw edema induced by carrageenin in rats, ear edema induced by dimethylbenzene, and increased capillary permeability in the mouse abdominal cavity induced by acetic acid. Moreover, TCSauI had inhibitory activities against the writhing reaction induced by acetic acid and the hot plate reaction in mice. The present study provided evidence first that TCSauI has antiinflammatory and analgesic activities, suggesting the potential of the tissue culture technique to substitute for wild S. involucrata in the pharmaceutical industry.

HIV-1-infected monocyte/macrophages located in lymph nodes and tissues are highly productive sources of HIV-1 and may function as a persistent reservoir contributing to the rebound viremia observed after highly active antiretroviral therapy is stopped. Mechanisms activating latently infected, primary monocyte/macrophages to produce HIV-1 were investigated using monocytes isolated from a transgenic mouse line carrying a full-length proviral clone of a monocyte-tropic HIV-1 isolate, HIV-1(JR-CSF), regulated by the endogenous long terminal repeat (LTR) (JR-CSF mice). Granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with lipopolysaccharide (LPS) induced infectious HIV-1 production by JR-CSF mouse monocytes over 10-fold and 100-fold higher than that stimulated by GM-CSF or LPS alone, respectively. We examined mechanisms of GM-CSF synergy with LPS and demonstrated that GM-CSF up-regulated the LPS receptor, TLR-4, and also synergized with LPS to activate mitogen-activated protein (MAP) kinase/ERK kinase and the Sp1 transcription factor. Inhibitors of either MAP kinase/ERK kinase or p38 kinase but not PI 3-kinase potently suppressed GM-CSF and LPS-induced HIV-1 production by JR-CSF mouse monocytes. Because Sp1 is activated by both the MAP kinase/ERK kinase and p38 kinase pathways, we postulate that synergistic activation of these pathways by GM-CSF and LPS induced sufficient levels of Sp1 to activate the HIV-1 LTR in a Tat-independent manner and induced HIV-1 production by JR-CSF mouse monocytes. Thus, our study delineated the pathway of HIV-1 LTR activation by GM-CSF and LPS and indicated that JR-CSF transgenic mice may provide a new in vitro and in vivo system for investigating the mechanism by which inflammatory and infectious stimuli activate HIV-1 production from latently infected monocytes.

Background & Objective: Survivin abnormally overexpresses in a variety of human tumors, it may play an important role in the development of tumor. This study was designed to investigate the inhibitory effects of survivin antisense oligonucleotide (ASODN) on human ovarian carcinoma cell SKOV3 in vivo and its mechanism., Methods: SKOV3 cells were transfected with survivin ASODN mediated by DOTAP liposome reagent, MTT method was used to observe the inhibitory rate, Western blot analysis was used to determine relating gene expression. Flow cytometry, DNA ladder analysis, and DAPI staining were used to examine cell apoptosis. Kinase activity test was used to examine the changes of caspase-3 activity., Results: The expression of survivin in SKOV3 cells decreased after transfected with survivin ASODN. Survivin ASODN has obviously inhibited the growth of SKOV3 cells after transfection. The inhibitory rate of 1000 ng/ml ASODN transfection group was (60.30+/-2.95)%, which is obviously higher than control group (P< 0.05). Survivin ASODN transfection induced cell cycle arrest in G1 phrase, while the apoptotic rate increased from 0.65% to 32.10%. Caspase-3 activity (0.998+/-0.001) increased significantly after transfected with survivin ASODN (P< 0.01)., Conclusion: Survivin ASODN,which can inhibit human ovarian carcinoma SKOV3 cells proliferation and induce apoptosis, is a prospective anti-cancer drug.

Objective: To investigate the role of extracellular regulated kinase (ERK1/2) pathway in cisplatin-induced apoptosis in human ovarian carcinoma cells., Methods: Cisplatin-induced apoptosis were stained with DAPI and was assessed microscopically in human epithelial adenocarcinoma ovarian cell line SKOV3 cells. ERK activation was determined by Western blotting using an anti-phospho-ERK antibody to detect ERK activity. The effect of PD98059 on ERK activity induced by cisplatin was detected by MTT assay., Results: Marked apoptosis of SKOV3 cells resulted from 48 hours treatment with 20 microg/mL cisplatin. Strong activation of ERK was led to by 15 microg/mL cisplatin. Dose response and time course of cisplatin induced apoptosis in SKOV3 cells. Cisplatin-induced ERK activation occurred at 12 hours and increased to highest induction at 24 hours by Western blotting. The effect of PD 98059 on ERK activity induced by cisplatin at the concentration of 100 micromol/L PD 98059. Statistically significant decreased in cell survival were observed with 100 micromol/L PD 98059 at 15 and 20 microg/mL cisplatin (P < 0.05)., Conclusions: Cisplatin activates the ERK signaling pathway in ovarian cancer cell line SKOV3. Inhibition of ERK activity enhances sensitivity to cisplatin cytotoxity in ovarian cancer cell line SKOV3. Evaluation of ERK activity could be useful in predicting which ovarian cancer will response most favorably to cisplatin therapy.

Objective: In recent years, many studies have been published regarding telomere length and telomerase activity in malignant tissues. However, it is not enough that telomere length and telomerase activity in gynecologic cancers have been measured at same time. We investigated the relationship between telomere length and telomerase activity in gynecologic cancers., Methods: A total of 52 gynecologic cancers (15 ovarian cancers, 23 endometrial cancers, 14 cervical cancers) were obtained at the time of surgery. The specimens were analyzed for telomerase activity and telomere length with the TRAP(EZE) ELISA kit and Southern blot, respectively., Results: Telomerase activity was detected in 42 of 50 (84.0%) of all evaluable specimens, in 11/15 (73.3%) ovarian, 18/22 (81.8%) endometrial, and in 13/13 (100%) cervical cancers. The difference of positive strength (DeltaA value) between stage I and III was statistically significant (P = 0.01, ANOVA test). Changes in telomere length by shortening or elongation were detected in 35 of 52 (67.3%) tumors, in 9/15 (60.0%) ovarian, 17/23 (73.9%) endometrial, and 9/14 (64.3%) cervical cancers. There was no detectable relationship between telomere length and stage of disease, pathologic diagnosis (ovarian, endometrial, and cervical cancers), or telomerase activity., Conclusions: There was no relationship between telomerase activity and telomere length. The clinical significance of telomere length appears to be limited in gynecologic cancers.