Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries.

Background: A 9-valent human papillomavirus-6/11/16/18/31/33/45/52/58 (9vHPV) vaccine extends coverage to 5 next most common oncogenic types (31/33/45/52/58) in cervical cancer versus quadrivalent HPV (qHPV) vaccine. We describe efficacy, immunogenicity, and safety in Asian participants (India, Hong Kong, South Korea, Japan, Taiwan, and Thailand) from 2 international studies: a randomized, double-blinded, qHPV vaccine-controlled efficacy study (young women aged 16-26 years; NCT00543543; Study 001); and an immunogenicity study (girls and boys aged 9-15 years; NCT00943722; Study 002). Methods: Participants (N = 2519) were vaccinated at day 1 and months 2 and 6. Gynecological samples (Study 001 only) and serum were collected for HPV DNA and antibody assessments, respectively. Injection-site and systemic adverse events (AEs) were monitored. Data were analyzed by country and vaccination group. Results: 9vHPV vaccine prevented HPV-31/33/45/52/58-related persistent infection with 90.4%-100% efficacy across included countries. At month 7, ≥97.9% of participants seroconverted for each HPV type. Injection-site AEs occurred in 77.7%-83.1% and 81.9%-87.5% of qHPV and 9vHPV vaccine recipients in Study 001, respectively, and 62.4%-85.7% of girls/boys in Study 002; most were mild to moderate. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Asian participants. Data support 9vHPV vaccination programs in Asia. Clinical Trials Registration: NCT00543543; NCT00943722.

Dysregulation of microRNA-204 mediates migration and invasion of endometrial cancer by regulating FOXC1.

MicroRNAs (miRNAs) regulate mRNA stability and protein expression, and certain miRNAs have been demonstrated to act either as oncogenes or tumor suppressors. Differential miRNA expression signatures have been documented in many human cancers but the role of miRNAs in endometrioid endometrial cancer (EEC) remains poorly understood. This study identifies significantly dysregulated miRNAs of EEC cells, and characterizes their impact on the malignant phenotype. We studied the expression of 365 human miRNAs using Taqman low density arrays in EECs and normal endometriums. Candidate differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of highly dysregulated miRNAs was examined in vitro through the effect of anti-/pre-miRNA transfection on the malignant phenotype. We identified 16 significantly dysregulated miRNAs in EEC and 7 of these are novel findings with respect to EEC. Antagonizing the function of miR-7, miR-194 and miR-449b, or overexpressing miR-204, repressed migration, invasion and extracellular matrix-adhesion in HEC1A endometrial cancer cells. FOXC1 was determined as a target gene of miR-204, and two binding sites in the 3'-untranslated region were validated by dual luciferase reporter assay. FOXC1 expression was inversely related to miR-204 expression in EEC. Functional analysis revealed the involvement of FOXC1 in migration and invasion of HEC1A cells. Our results present dysfunctional miRNAs in endometrial cancer and identify a crucial role for miR-204-FOXC1 interaction in endometrial cancer progression. This miRNA signature offers a potential biomarker for predicting EEC outcomes, and targeting of these cancer progression- and metastasis-related miRNAs offers a novel potential therapeutic strategy for the disease.

T-cell response to human papillomavirus type 52 L1, E6, and E7 peptides in women with transient infection, cervical intraepithelial neoplasia, and invasive cancer.

The E6 and E7 proteins encoded by human papillomaviruses (HPV) are prime targets for therapeutic vaccine development. Ninety-five women with HPV 52 infection (33 transient infections, 17 cervical intraepithelial neoplasia grade II, 15 cervical intraepithelial neoplasia grade III, and 30 invasive cervical cancers) were examined for T-cell responses using interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT) assay. Of the 29 peptides (13 L1, 10 E6, and 6 E7) screened positive by an in vitro peptide-binding assay, 14 were positive by the IFN-γ ELISPOT assay. Positive epitopes for HLA A11 were located at amino acid positions 103-111, 332-340, 342-350, and 373-381 of the L1 protein; and at 27-35 and 86-94 of the E6 protein; and at 1-9 and 27-35 of the E7 protein. A24-specific epitopes included 60-68 and 98-106 of the L1 protein, 42-50 and 59-67 of the E6 protein, and 24-32 of the E7 protein. Only one epitope (99-107) of the E6 protein showed positive responses for HLA A2 subjects. Overall, T-cell responses against L1 were observed mainly in subjects who had cleared infection; whereas responses against E6 and E7 were confined mainly to subjects who had developed cervical neoplasia. The proportion of subjects showing detectable T-cell responses was low across all grades of cervical neoplasia suggesting that immune evasion mechanisms had set on early in the course of disease progression. This study provides the first set of T-cell epitopes mapped for HPV 52, which can be considered for further evaluation as targets for immunotherapy.

CHD5 Downregulation Associated with Poor Prognosis in Epithelial Ovarian Cancer.

BACKGROUND: The CHD5 gene located on 1p36 encodes a protein-chromodomain helicase DNA-binding protein 5. CHD5 has been shown to be a tumor suppressor gene candidate. This study investigated the involvement of CHD5 in ovarian cancer and its clinicopathological significance. METHODS: CHD5 expression in ovarian cancer and its counterpart were determined by quantitative RT-PCR. The correlation of CHD5 expression to clinicopathological features of the tumor was analyzed. RESULTS: CHD5 expression was downregulated by at least twofold in 32 of 72 (41%) invasive epithelial ovarian carcinomas when compared to 12 controls in Hong Kong Chinese women. CHD5 downregulation was correlated to clinical status (p < 0.05), but not to patient age, tumor type and grade, recurrence and clinical stage (p > 0.05). Survival analysis showed that patients with CHD5 downregulation in their tumors were associated with shorter disease-free and total survival times compared to those without CHD5 downregulation (p < 0.05). Cox proportional-hazards regression analysis indicated that downregulation of CHD5 is an independent adverse prognostic factor in ovarian cancer. CONCLUSION: This study shows that CHD5 is downregulated in a certain number of ovarian cancers and appears to be an adverse predictor candidate of ovarian cancer disease-free and total survival.

Laparoscopic sacrocolpopexy for the treatment of vaginal vault prolapse: with or without robotic assistance.

OBJECTIVE: To assess perioperative and medium-term outcome after laparoscopic sacrocolpopexy with or without robotic assistance for vaginal vault prolapse in a Hong Kong tertiary centre. DESIGN: Retrospective study. SETTING: An urogynaecology unit in Hong Kong. PATIENTS: All women who underwent laparoscopic sacrocolpopexy with or without robotic assistance for vaginal vault prolapse from March 2005 to May 2010. MAIN OUTCOME MEASURES: The perioperative and medium-term outcomes. RESULTS: A total of 36 women underwent the operation during the study period. The mean operating time was 205 minutes, mean blood loss was 144 mL. The median hospital stay was 4 days. Two women required early re-operation but recovered fully. In all, 35 women were followed up for 29 (standard deviation, 19) months. Three of them (9%) had a recurrence of stage II prolapse, but there was statistically significant improvement in the pelvic organ prolapse quantification assessment for all three compartments of the vagina, and the length of vagina was well preserved. There were no mesh exposure or erosions. The overall objective cure rate of 91% (32/35) was high, and 91% (32/35) were satisfied with the operative outcome. Stress incontinence and voiding difficulty were significantly reduced. CONCLUSION: Laparoscopic sacrocolpopexy for vaginal vault prolapse is safe, although complications arising from concomitant surgery should not be neglected. High rates of objective cures and patient satisfaction were achieved. There were no mesh exposure or erosions. Laparoscopic sacrocolpopexy should be considered an option for women with vaginal vault prolapse.

Comparison of the effects of 2,5-dimethoxy-4-iodoamphetamine and D-amphetamine on the ability of rats to discriminate the durations and intensities of light stimuli.

Rats' ability to discriminate durations is disrupted by the monoamine-releasing agent D-amphetamine and the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). It is unknown whether this effect is specific for temporal discrimination or reflects general disruption of stimulus control. This experiment addressed this question by comparing the effects of D-amphetamine and DOI on temporal discrimination and discrimination along a nontemporal dimension, light intensity. Twelve rats responded on a schedule in which a light (intensity 22 cd/m) was presented for t seconds (2.5-47.5 s), after which levers A and B were presented. Responses on A were reinforced when t was less than 25 s, and responses on B were reinforced when t was greater than 25 s. Twelve rats responded on a similar schedule in which a light of intensity i (3.6-128.5 cd/m) was presented for 25 s. Responses on A were reinforced when i was less than 22 cd/m, and responses on B were reinforced when i was greater than 22 cd/m. Logistic functions were fitted and psychophysical parameters estimated [T50, I50 (central tendency of temporal or light-intensity discrimination); Weber fraction (relative discriminative precision)]. D-Amphetamine (0.2-0.8 mg/kg) increased the Weber fraction for temporal and light-intensity discrimination; DOI (0.625-0.25 mg/kg) increased it for temporal discrimination only. Both drugs increased T50; neither altered I50. D-Amphetamine and DOI have similar effects on temporal discrimination but different effects on light-intensity discrimination. The increase in T50 may reflect the impairment of sustained attention during prolonged stimulus presentation.

Quantitative analysis of the effect of lesions of the subthalamic nucleus on intertemporal choice: further evidence for enhancement of the incentive value of food reinforcers.

Recent evidence suggests that the subthalamic nucleus (STN) is involved in regulating the incentive value of food reinforcers. The objective of this study was to examine the effect of lesions of the STN on intertemporal choice (choice between reinforcers differing in size and delay). Rats with bilateral quinolinic acid-induced lesions of the STN (n = 15) or sham lesions (n = 14) were trained in a discrete-trials progressive delay schedule to press levers A and B for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after a delay d(B). d(B) increased across blocks of trials; d(A) was manipulated across phases of the experiment. Indifference delay, d(B(50)) (value of d(B) corresponding to 50% choice of B), was estimated for each rat in each phase, and linear indifference functions (d(B(50)) vs. d(A)) were derived. The STN-lesioned group showed a flatter slope of the indifference function (implying higher instantaneous reinforcer values) than the sham-lesioned group; the intercepts did not differ between the groups. The results agree with recent evidence for a role of the STN in incentive value. Unlike some earlier studies, these results do not indicate a role of the STN in delay discounting.

Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling.

Endometrial cancer is the third most common gynecologic malignancy and the ninth most common malignancy for females overall in Hong Kong. Approximately 80% or more of these cancers are endometrioid endometrial adenocarcinomas. The aim of this study was to reveal genes contributing to the development of endometrioid endometrial cancer, which may impact diagnosis, prognosis and treatment of the disease. Whole-genome gene expression analysis was completed for a set of 55 microdissected sporadic endometrioid endometrial adenocarcinomas and 29 microdissected normal endometrium specimens using the Affymetrix Human U133 Plus 2.0 oligonucleotide microarray. Selected genes of interest were validated by quantitative real-time-polymerase chain reaction (qRT-PCR). Pathway analysis was performed to reveal gene interactions involved in endometrial tumorigenesis. Unsupervised hierarchical clustering displayed a distinct separation between the endometrioid adenocarcinomas and normal endometrium samples. Supervised analysis identified 117 highly differentially regulated genes (>or=4.0-fold change), which distinguished the endometrial cancer specimens from normal endometrium. Twelve novel genes including DKK4, ZIC1, KIF1A, SAA2, LOC16378, ALPP2, CCL20, CXCL5, BST2, OLFM1, KLRC1 and MBC45780 were deregulated in the endometrial cancer, and further validated in an independent set of 56 cancer and 29 normal samples using qRT-PCR. In addition, 10 genes were differentially regulated in late-stage cancer, as compared to early-stage disease, and may be involved in tumor progression. Pathway analysis of the expression data from this tumor revealed an interconnected network consisting of 21 aberrantly regulated genes involved in angiogenesis, cell proliferation and chromosomal instability. The results of this study highlight the molecular features of endometrioid endometrial cancer and provide insight into the events underlying the development and progression of endometrioid endometrial cancer.

Increase of integration events and infection loads of human papillomavirus type 52 with lesion severity from low-grade cervical lesion to invasive cancer.

Infection load and the integration of human papillomaviruses (HPV) have been implicated as determinants for oncogenesis, but whether variation among different HPV types exists remains unclear. We investigated 91 women infected with HPV type 52 (HPV-52), a type that is rare worldwide but common in East Asia. The median viral load increased with the severity of the lesion (248 copies/cell equivalent for normal/cervical intraepithelial neoplasia [CIN] grade 1, 402 copies/cell equivalent for CIN 2, 523 copies/cell equivalent for CIN 3, and 1,435 copies/cell equivalent for invasive cancer). The proportion of specimens with integration increased significantly with the severity of the lesion (P < 0.001). The viral load was associated with the physical status of the viral genome, with higher levels for the pure episomal form (P = 0.001). Infection status should be considered when interpreting viral load data for HPV-52, as single infections with this HPV type were found to have marginally higher viral loads than coinfections (P = 0.051). All except one sample had E2 disruption restricted to only a part of the gene. Integration is a critical step in HPV-52-induced carcinogenesis. The profile of E2 disruption was different from that described for HPV-16, with the amino-terminal region being most frequently involved. Selecting the appropriate E2 region for amplification is critical in studying the integration of HPV-52. In summary, the HPV-52 viral load and the integrated proportion increased with the severity of the cervical lesions but had a different pattern than that of HPV-16.

Effect of quinolinic acid-induced lesions of the nucleus accumbens core on performance on a progressive ratio schedule of reinforcement: implications for inter-temporal choice.

RATIONALE: The nucleus accumbens core (AcbC) is believed to contribute to the control of operant behaviour by reinforcers. Recent evidence suggests that it is not crucial for determining the incentive value of immediately available reinforcers, but is important for maintaining the values of delayed reinforcers. OBJECTIVE: This study aims to examine the effect of AcbC lesions on performance on a progressive-ratio schedule using a quantitative model that dissociates effects of interventions on motor and motivational processes (Killeen 1994 Mathematical principles of reinforcement. Behav Brain Sci 17:105-172). MATERIALS AND METHODS: Rats with bilateral quinolinic acid-induced lesions of the AcbC (n = 15) or sham lesions (n = 14) were trained to lever-press for food-pellet reinforcers under a progressive-ratio schedule. In Phase 1 (90 sessions) the reinforcer was one pellet; in Phase 2 (30 sessions), it was two pellets; in Phase 3, (30 sessions) it was one pellet. RESULTS: The performance of both groups conformed to the model of progressive-ratio performance (group mean data: r2 > 0.92). The motor parameter, delta, was significantly higher in the AcbC-lesioned than the sham-lesioned group, reflecting lower overall response rates in the lesioned group. The motivational parameter, a, was sensitive to changes in reinforcer size, but did not differ significantly between the two groups. The AcbC-lesioned group showed longer post-reinforcement pauses and lower running response rates than the sham-lesioned group. CONCLUSIONS: The results suggest that destruction of the AcbC impairs response capacity but does not alter the efficacy of food reinforcers. The results are consistent with recent findings that AcbC lesions do not alter sensitivity to reinforcer size in inter-temporal choice schedules.

Effect of disconnecting the orbital prefrontal cortex from the nucleus accumbens core on inter-temporal choice behaviour: a quantitative analysis.

Previous experiments showed that destruction of the orbital prefrontal cortex (OPFC) or the nucleus accumbens core (AcbC) in rats altered choice between two delayed food reinforcers. Application of a quantitative model of inter-temporal choice suggested that lesions of either structure increased the delay-dependent degradation of reinforcer value (delay discounting); destruction of the OPFC (but not the AcbC) also increased the relative value of the larger reinforcer. This experiment examined the effect of disconnecting the OPFC from the AcbC on inter-temporal choice. Rats received excitotoxin-induced contralateral lesions of the OPFC and AcbC (disconnection), severing of the anterior corpus callosum (callosotomy), a combined lesion (disconnection+callosotomy) or sham lesions. They were trained in a discrete-trials progressive delay schedule to press levers A and B for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after a delay d(B). d(B) increased across blocks of trials; d(A) was manipulated across phases of the experiment. Indifference delay, d(B50) (value of d(B) corresponding to 50% choice of B), was estimated for each rat in each phase, and linear indifference functions (d(B50)vs. d(A)) were derived. The disconnection+callosotomy group showed a lower intercept of the indifference function (implying a higher rate of delay discounting) than the sham-lesioned group; the disconnection group showed a similar but less robust effect, whereas the callosotomy group did not differ significantly from the sham-lesioned group. The results suggest that OPFC-AcbC connections are involved in delay discounting of food reinforcers, but provide no evidence for an involvement of OPFC-AcbC connections in regulating sensitivity to reinforcer size.

Tolerance to the effect of 2,5-dimethoxy-4-iodoamphetamine (DOI) on free-operant timing behaviour: interaction between behavioural and pharmacological mechanisms.

RATIONALE: The psychostimulant d-amphetamine, the D(2/3) dopamine receptor agonist quinpirole and the 5-HT(2) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) have similar effects on free-operant timing behaviour. There is evidence that tolerance develops to the effects of psychostimulants on timing performance during chronic treatment; this tolerance is generally attributed to behavioural adaptation rather than to pharmacological desensitisation. There have been no previous investigations of tolerance to the effect of DOI on free-operant timing behaviour. OBJECTIVE: To demonstrate tolerance to DOI's effect on timing performance and to examine the nature of this tolerance. MATERIALS AND METHODS: Rats were trained under the free-operant psychophysical procedure to press two levers (A and B) in 80-s trials in which reinforcement was provided intermittently for responding on A in the first half and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 8-s epochs of the trials; logistic functions were fitted to the data from each rat for the derivation of timing indices (T (50) [time corresponding to %B = 50]; Weber fraction). RESULTS: In experiment 1, DOI (0.25 mg kg(-1)) reduced T (50) compared to vehicle; tolerance to this effect was seen after repeated daily treatments with DOI if the rats were exposed to behavioural training during the period of treatment but not if the repeated treatments took place during a 'holiday' from behavioural training. In experiment 2, repeated treatment with DOI resulted in tolerance to the effect of DOI on T (50) and cross-tolerance to the effect of d-amphetamine (0.4 mg kg(-1)), but no cross-tolerance was seen to the effect of quinpirole (0.08 mg kg(-1)). CONCLUSIONS: The results indicate that behavioural adaptation is involved in the development of tolerance to DOI's effect on timing. The finding of cross-tolerance to d-amphetamine but not to quinpirole suggests that the reduction of T (50) in the free-operant psychophysical procedure may be brought about by two distinct pharmacological mechanisms, one activated by DOI and d-amphetamine, and the other by quinpirole.

Evidence for the sensitivity of operant timing behaviour to stimulation of D1 dopamine receptors.

RATIONALE: Temporal differentiation of operant behaviour is sensitive to dopaminergic manipulations. Previous studies using the fixed-interval peak procedure implicated D(2)-like dopamine receptors in these effects. However, recent findings suggest that d-amphetamine alters timing performance on the free-operant psychophysical procedure via D(1)-like receptors. It is not known whether this effect of d-amphetamine is mimicked by direct D(1)-like receptor stimulation. OBJECTIVE: The effects of a D(1)-like receptor agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine (SKF-81297) on performance on the free-operant psychophysical procedure and the interaction between SKF-81297 and a D(1)-like receptor antagonist 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566) and a D(2)-like receptor antagonist haloperidol, were examined. MATERIALS AND METHODS: Rats were trained to respond on two levers (A and B) under a free-operant psychophysical schedule, in which sucrose reinforcement was provided intermittently for responding on A during the first half and on B during the second half of 50-s trials. Logistic psychometric functions were fitted to the relative response rate data (percent responding on B [%B] vs time from trial onset [t]) under each treatment condition, and quantitative indices of timing (T(50) [value of t corresponding to %B = 50] and the Weber fraction [(T(75)-T(25))/2T(50); T(25) and T(75) are values of t corresponding to %B = 25 and %B = 75] were compared among treatments. RESULTS: SKF-81297 (0.8 mg kg(-1)) reduced T(50); this effect was antagonized by SKF-83566 (0.03 mg kg(-1)) but not by haloperidol (0.05, 0.1 mg kg(-1)). CONCLUSIONS: Stimulation of D(1)-like dopamine receptors affects performance in the free-operant psychophysical procedure.

Effects of quinolinic acid-induced lesions of the nucleus accumbens core on inter-temporal choice: a quantitative analysis.

RATIONALE: There is evidence that lesions of the nucleus accumbens core (AcbC) promote preference for smaller earlier reinforcers over larger delayed reinforcers in inter-temporal choice paradigms. It is not known whether this reflects an effect of the lesion on the rate of delay discounting, on sensitivity to reinforcer magnitude, or both. AIM: We examined the effect of AcbC lesions on inter-temporal choice using a quantitative method that allows effects on delay discounting to be distinguished from effects on sensitivity to reinforcer size. MATERIALS AND METHODS: Sixteen rats received bilateral quinolinic acid-induced lesions of the AcbC; 14 received sham lesions. They were trained under a discrete-trials progressive delay schedule to press two levers (A and B) for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after d(B). d(B) increased across blocks of trials, while d(A) was manipulated across phases of the experiment. Indifference delay d(B(50)) (value of d(B) corresponding to 50% choice of B) was estimated in each phase, and linear indifference functions (d(B(50)) vs d(A)) derived. RESULTS: d(B(50)) increased linearly with d(A) (r(2) > 0.95 in each group). The intercept of the indifference function was lower in the lesioned than the sham-lesioned group; slope did not differ between groups. The lesioned rats had extensive neuronal loss in the AcbC. CONCLUSIONS: The results confirm that lesions of the AcbC promote preference for smaller, earlier reinforcers and suggest that this reflects an effect of the lesion on the rate of delay discounting.

Effect of quinpirole on timing behaviour in the free-operant psychophysical procedure: evidence for the involvement of D2 dopamine receptors.

RATIONALE: Operant timing behaviour is sensitive to dopaminergic manipulations. It has been proposed that this effect is mediated principally by D(2)-like dopamine receptors. However, we recently found that the effect of d-amphetamine on timing in the free-operant psychophysical procedure was mediated by D(1)-like dopamine receptors. It has not been established whether stimulation of D(2)-like receptors affects timing in this schedule. OBJECTIVE: To examine the effects of a D(2)-like receptor agonist quinpirole on second-range timing and the ability of dopamine receptor antagonists to reverse quinpirole's effects. MATERIALS AND METHODS: Rats responded on two levers (A and B) under a free-operant psychophysical schedule in which reinforcement was provided intermittently for responding on A during the first half, and B during the second half, of 50-s trials. Logistic functions were fitted to the relative response rates [percent responding on B (%B) vs time (t)] under each treatment; quantitative timing indices [T (50) (value of t when %B = 50) and Weber fraction] were compared among treatments. RESULTS: Quinpirole (0.04, 0.08 mg kg(-1)) reduced T (50). This effect was attenuated by D(2)-like receptor antagonists haloperidol (0.05, 0.1 mg kg(-1)), eticlopride (0.04, 0.08 mg kg(-1)) and sulpiride (30, 60 mg kg(-1)), but not by the D(3) receptor-preferring antagonist nafadotride (0.5, 1 mg kg(-1)), the D(4) receptor antagonist L-745870 (1, 3 mg kg(-1)) or the D(1)-like receptor antagonist SKF-83566 (0.015 mg kg(-1)). CONCLUSIONS: Results suggest that quinpirole reduced T (50) via an action at D(2) receptors. D(1)-like and D(2)-like receptors may mediate behaviourally similar but pharmacologically distinct effects on timing behaviour.

Patients with malignant or pre-malignant cervical lesion have increased risk of becoming hepatitis B carrier.

Human Papillomavirus (HPV) and Hepatitis B virus (HBV) are known aetiology of cervical and hepatocellular carcinoma, respectively. Both diseases share a similar clinical course, that is, the vast majority of those infected by these two viruses can eradicate the viruses spontaneously. A small sub-group who fails to clear the virus becomes chronic carrier and can progress to carcinoma many years later. We postulated that patients with pre-malignant or malignant cervical lesion are at increased risk of becoming chronic HBV carrier if infected, which may be attributed to inherent immunological deficiency against viral infection. We tested HBV carrier status from 288 patients with cervical carcinoma, 242 patients with high grade cervical intra-epithelial neoplasia (CIN) and 311 women with neither of the above conditions as control subjects. The HBV carrier rate in the Cancer Group, CIN Group and Control Group was 21.4%, 24.1% and 10.6%. The carrier rate was significantly higher in both the Cancer Group (p<0.01) and the CIN Group (p<0.01), compared to the Control Group. Our study suggests that a common immunological mechanism is involved in eradication of HBV and HPV infections and inherent immuno-deficiency might lead to an association of HBV carrier status with cervical carcinoma. Further studies are needed to confirm our findings and delineate the mechanism involved.

Is aortic lymphadenectomy necessary in the management of endometrial carcinoma?

OBJECTIVE: To evaluate the role of aortic lymphadenectomy in the management of endometrial carcinoma. METHODS: Clinical notes of 163 patients with endometrial carcinoma were reviewed. All patients had peritoneal cytology, total abdominal hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy with or without aortic lymphadenectomy. RESULTS: Seventy-five (46.0%) patients had pelvic lymphadenectomy alone whereas 88 (54.0%) had both pelvic and aortic lymphadenectomy. Thirty-five (21.5%) patients had nodal metastases with positive pelvic and aortic nodes in 26 (16.0%) and 24 (27.3%) patients, respectively. Isolated aortic metastases were found in 17 cases (19.3%). Among 35 patients with nodal metastases, recurrence developed in 15 (42.9%) patients and all except one died within five to 50 months. The remaining patients had a median disease-free period of 55 months (13-93 months). The recurrence rate was higher (63.6%) among patients with upper aortic lymph node metastases, and all those who recurred died of disease within seven to 28 months. CONCLUSIONS: Our data suggest that aortic lymphadenectomy provides both diagnostic and therapeutic value in the management of endometrial carcinoma with high metastatic risk. After surgical removal and adjuvant radiotherapy, patients with nodal metastases achieved a better survival chance.

A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNFα-TGFα-EGFR.

Peritoneum is the most common site for ovarian cancer metastasis. Here we investigate how cancer epigenetics regulates reciprocal tumor-stromal interactions in peritoneal metastasis of ovarian cancer. Firstly, we find that omental stromal fibroblasts enhance colony formation of metastatic ovarian cancer cells, and de novo expression of transforming growth factor-alpha (TGF-α) is induced in stromal fibroblasts co-cultured with ovarian cancer cells. We also observed an over-expression of tumor necrosis factor-alpha (TNF-α) in ovarian cancer cells, which is regulated by promoter DNA hypomethylation as well as chromatin remodeling. Interestingly, this ovarian cancer-derived TNF-α induces TGF-α transcription in stromal fibroblasts through nuclear factor-κB (NF-κB). We further show that TGF-α secreted by stromal fibroblasts in turn promotes peritoneal metastasis of ovarian cancer through epidermal growth factor receptor (EGFR) signaling. Finally, we identify a TNFα-TGFα-EGFR interacting loop between tumor and stromal compartments of human omental metastases. Our results therefore demonstrate cancer epigenetics induces a loop of cancer-stroma-cancer interaction in omental microenvironment that promotes peritoneal metastasis of ovarian cancer cells via TNFα-TGFα-EGFR.

Effects of d-amphetamine and DOI (2,5-dimethoxy-4-iodoamphetamine) on timing behavior: interaction between D1 and 5-HT2A receptors.

RATIONALE: The dopamine-releasing agent d-amphetamine and the 5-HT(2) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) have similar effects on free-operant timing behavior. The selective D(1) dopamine receptor antagonist 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566), but not the D(2) dopamine receptor antagonist haloperidol, can antagonize the effect of d-amphetamine, and the selective 5-HT(2A) receptor antagonist (+/-)2,3-dimethoxyphenyl-1-(2-(4-piperidine)-methanol (MDL-100907) can antagonize the effect of DOI. However, it is not known whether the effect of d-amphetamine can be reversed by MDL-100907 and the effect of DOI by dopamine receptor antagonists. OBJECTIVE: The objective of this work is to examine the interactions of d-amphetamine and DOI with MDL-100907, SKF-83566, and haloperidol on timing performance. MATERIALS AND METHODS: Rats (n = 12-15 per experiment) were trained under the free-operant psychophysical procedure to press two levers (A and B) in 50-s trials in which reinforcement was provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic functions were fitted to the data from each rat for the derivation of timing indices [T (50) (time corresponding to %B = 50); Weber fraction]. Rats were treated systemically with d-amphetamine or DOI, alone and in combination with haloperidol, SKF-83566, or MDL-100907. RESULTS: d-Amphetamine (0.4 mg kg(-1)) reduced T (50) compared to vehicle; this effect was antagonized by SKF-83566 (0.03 mg kg(-1)) and MDL-100907 (0.5 mg kg(-1)), but not by haloperidol (0.05, 0.1 mg kg(-1)). DOI (0.25 mg kg(-1)) also reduced T (50); this effect was reversed by MDL-100907 (0.5 mg kg(-1)), but not by SKF-83566 (0.03 mg kg(-1)) or haloperidol (0.05 mg kg(-1)). CONCLUSIONS: The results suggest that both 5-HT(2A) and D(1) receptors, but not D(2) receptors, are involved in d-amphetamine's effect on timing behavior in the free-operant psychophysical procedure. DOI's effect on timing is mediated by 5-HT(2A) receptors, but neither D(1) nor D(2) receptors are involved in this effect.