In diagnostic medicine, estimating the diagnostic accuracy of a group of raters or medical tests relative to the gold standard is often the primary goal. When a gold standard is absent, latent class models where the unknown gold standard test is treated as a latent variable are often used. However, these models have been criticized in the literature from both a conceptual and a robustness perspective. As an alternative, we propose an approach where we exploit an imperfect reference standard with unknown diagnostic accuracy and conduct sensitivity analysis by varying this accuracy over scientifically reasonable ranges. In this article, a latent class model with crossed random effects is proposed for estimating the diagnostic accuracy of regional obstetrics and gynaecological (OB/GYN) physicians in diagnosing endometriosis. To avoid the pitfalls of models without a gold standard, we exploit the diagnostic results of a group of OB/GYN physicians with an international reputation for the diagnosis of endometriosis. We construct an ordinal reference standard based on the discordance among these international experts and propose a mechanism for conducting sensitivity analysis relative to the unknown diagnostic accuracy among them. A Monte-Carlo EM algorithm is proposed for parameter estimation and a BIC-type model selection procedure is presented. Through simulations and data analysis we show that this new approach provides a useful alternative to traditional latent class modeling approaches used in this setting.
Diagnostic error; Imperfect tests; Prevalence; Sensitivity; Specificity; Model selection
In Bacillus thuringiensis, a novel N-acetylmuramoyl-l-alanine amidase gene (named cwlB) was detected, and the CwlB protein was purified and characterized. Reverse transcription-PCR (RT-PCR) results indicated that cwlB and an upstream gene (named cwlA) formed one transcriptional unit. 5′ rapid amplification of cDNA ends (5′-RACE)-PCR and transcriptional fusions with the lacZ gene indicated that transcription of the operon was directed by a promoter, PcwlA, which is located upstream from the cwlA gene and that the transcription start site is a single 5′-end nucleotide residue T located 25 nucleotides (bp) upstream from the cwlA translational start codon. Moreover, the activity of PcwlA was controlled by σK. Morphological analysis suggested that the mutation of cwlB could delay spore release compared to the timing of spore release in the wild-type strain. Western blot assay demonstrated that purified CwlB bound to the B. thuringiensis cell wall. Observations with laser confocal microscopy and a green fluorescent protein-based reporter system demonstrated that the CwlB protein localizes to the cell envelope. All results suggest that the CwlB protein is involved in mother cell lysis in B. thuringiensis.
Recent evidence highlights the therapeutic potential of peroxisome proliferator–activated receptor-δ (PPARδ) agonists to increase insulin sensitivity in diabetes. However, the role of PPARδ in regulating vascular function is incompletely characterized. We investigate whether PPARδ activation improves endothelial function in diabetic and obese mice. PPARδ knockout (KO) and wild-type (WT) mice fed with high-fat diet and db/db mice were used as diabetic mouse models, compared with PPARδ KO and WT mice on normal diet and db/m+ mice. Endothelium-dependent relaxation (EDR) was measured by wire myograph. Flow-mediated vasodilatation (FMD) was measured by pressure myograph. Nitric oxide (NO) production was examined in primary endothelial cells from mouse aortae. PPARδ agonist GW1516 restored EDRs in mouse aortae under high-glucose conditions or in db/db mouse aortae ex vivo. After oral treatment with GW1516, EDRs in aortae and FMDs in mesenteric resistance arteries were improved in obese mice in a PPARδ-specific manner. The effects of GW1516 on endothelial function were mediated through phosphatidylinositol 3-kinase (PI3K) and Akt with a subsequent increase of endothelial nitric oxide synthase (eNOS) activity and NO production. The current study demonstrates an endothelial-protective effect of PPARδ agonists in diabetic mice through PI3K/Akt/eNOS signaling, suggesting the therapeutic potential of PPARδ agonists for diabetic vasculopathy.
The display of full-length antibody on the cell surface was achieved by fusing a transmembrane domain of the platelet-derived growth factor receptor (PDGFR) to the C-terminus of the heavy chain constant region. We also incorporated a furin cleavage site between the constant region and PDGFR transmembrane domain to obtain secreted antibodies. As a result, antibodies can be expressed simultaneously on the cell surface in a membrane-anchored version for screening and selecting through fluorescence-activated cell sorting (FACS) analysis, as well as in conditioned medium in a secreted version for function analysis.
Folypolyglutamate synthase (FPGS) catalyzes the polyglutamation of folates and antifolates, such as methotrexate (MTX), to produce highly active metabolites. FPGS tag SNP rs1544105C > T is located in the gene promoter. The aim of the present study was to investigate the impact of rs1544105 polymorphism on the treatment outcome in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
This study enrolled 164 children with BCP-ALL. We genotyped the FPGS SNP rs1544105, and analyzed the associations between its genotypes and treatment outcome. We also examined FPGS mRNA levels by real-time PCR in 64 of the 164 children, and investigated the function of this polymorphism on gene expression.
We found significantly poor relapse-free survival (RFS) (p = 0.010) and poor event-free survival (EFS) (p = 0.046) in carriers of CC genotype. Multivariable Cox regression analyses adjusted for possible confounding variables showed that, relative to the CT + TT genotypes, the CC genotype was an independent prognostic factor for poor RFS (hazard ratio [HR], 4.992.; 95% CI, 1.550-16.078; p = 0.007). No association was found between any toxicity and rs1544105 polymorphism. Quantitative PCR results showed that individuals with the T allele had lower levels of FPGS transcripts.
Our study indicates that FPGS rs1544105C > T polymorphism might influence FPGS expression and affect treatment outcome in BCP-ALL patients.
Folypolyglutamate synthase (FPGS); Methotrexate (MTX); Polymorphism; Treatment outcome; Acute lymphoblastic leukemia (ALL)
Obesity is a growing public health problem among reproductive-aged women, with consequences for chronic disease risk and reproductive and obstetric morbidities. Evidence also suggests that body shape (i.e., regional fat distribution) may be independently associated with risk, yet it is not known if women adequately perceive their shape. This study aimed to assess the validity of self-reported body size and shape figure drawings when compared to anthropometric measures among reproductive-aged women.
Self-reported body size was ascertained using the Stunkard nine-level figures and self-reported body shape using stylized pear, hourglass, rectangle, and apple figures. Anthropometry was performed by trained researchers. Body size and body mass index (BMI) were compared using Spearman's correlation coefficient. Fat distribution indicators were compared across body shapes for nonobese and obese women using analysis of variance (ANOVA) and Fisher's exact test. Percent agreement and kappa statistics were computed for apple and pear body shapes.
The 131 women studied were primarily Caucasian (81%), aged 32 years, with a mean BMI of 27.1 kg/m2 (range 16.6–52.8 kg/m2). The correlation between body size and BMI was 0.85 (p<0.001). Among nonobese women, waist-to-hip ratios (WHR) were 0.75, 0.75, 0.80, and 0.82 for pear, hourglass, rectangle, and apple, respectively (p<0.001). Comparing apples and pears, the percent agreement (kappa) for WHR≥0.80 was 83% (0.55).
Self-reported size and shape were consistent with anthropometric measures commonly used to assess obesity and fat distribution, respectively. Self-reported body shape may be a useful proxy measure in addition to body size in large-scale surveys.
Early metastasis is a major biological feature of pancreatic cancer. The current study examined whether silencing Slc38a1, a gene involved in energy metabolism, using short hairpin RNA (shRNA) could inhibit the growth, migration, and invasiveness of pancreatic cancer cells.
A series of Slc38a1 shRNAs were designed and cloned into the pGPU6/GFP/Neo vectors. An shRNA with the most efficacious inhibitory action on SCL38A1 expression (65% inhibition) upon screening in DH5α bacteria was used to transfect SW1990 human pancreatic cancer cells. Cell growth, migration, and invasiveness were examined using cell counting kit-8, Boyden chamber without and with Matrigel, respectively.
Transfection of SW1990 cells with the SLCs38A1 shRNA significantly decreased the proliferation (P<0.0001) and migratory potential (by 46.7%, P=0.0399) of the cancer cells. Invasiveness, however, was not affected.
Inhibiting Slc38a1 using shRNA technology could decrease the growth and migration of representative pancreatic cancer cells. However, the fact that invasiveness was not affected suggested that SLC38A1 is unlikely to be responsible for early metastasis.
Slc38a1; shRNA; pancreatic cancer
We have developed an amplified chemiluminescence turn-on sensing platform that relies on single-walled carbon nanotube for ultrasensitive DNA detection. This new type of assay exhibits high detection sensitivity over traditional biosensors three orders of magnitude and high specificity for target molecules.
The use of chemotherapy to treat cancer is effective, but chemoresistance reduces this efficacy. Chemotherapy resistance involves several mechanisms, including the cancer stem cell (CSC) concept. The aim of the present study was to assess whether paclitaxel-resistant epithelial ovarian carcinoma is capable of generating cells with CSC-like properties. Using the paclitaxel-resistant A2780/PTX cell line, it was demonstrated that high aldehyde dehydrogenase 1 (ALDH1) activity identifies CSCs from diverse sources. Furthermore, the A2780/PTX cells had a strong ability to form colonies in soft agar assays. Notably, it was demonstrated that the inhibition of the PI3K signaling pathway abolished colony formation. These data suggest that there is a link between paclitaxel resistance and CSC enrichment. It is possible that therapeutic benefits, such as the restoration of chemosensitivity or the suppression of tumorigenicity, may be enabled by gaining further insights into the mechanisms underlying chemoresistance and the generation of CSCs.
ovarian cancer; cancer stem cells; aldehyde dehydrogenase 1; paclitaxel; chemoresistance
To evaluate validity and responsiveness of PFDI and PFIQ short forms across 4 multi-center studies and develop conversion formulas between short and long versions.
1006 participants in 4 prospective studies of pelvic floor disorders completed long versions of the PFDI, PFIQ and SF-36 (or SF-12) at baseline and 3 and 12 months after treatment. Responses were used to calculate scores for the short versions. We calculated correlations between scale versions using Pearson’s correlation coefficient and compared their relative responsiveness using the standardized response mean.
PFDI and PFIQ short form scale scores demonstrated excellent correlations with long versions and similar responsiveness. Responsiveness was good to excellent for PFDI-20 urinary and prolapse scales, moderate for PFDI-20 colorectal scale and each of the PFIQ-7 scales, and poor for SF-36 (or SF-12) summary scores. Conversion formulas demonstrated excellent goodness of fit.
The long and short forms of the PFDI and PFIQ correlate well and have similar overall responsiveness in participants from 4 different prospective multicenter studies consisting of diverse patient populations with a broad range of pelvic floor disorders. The short forms provide a reliable and valid alternative in situations where reduced response burden is desired.
quality of life; pelvic organ prolapse; urinary incontinence; pelvic floor; questionnaires; responsiveness
The telomerase activity assay has been established for the detection of malignant pleural effusion (MPE), however, the overall diagnostic accuracy of the telomerase activity assay for MPE remains unclear. We performed a systematic search in the Pubmed, Embase and Cochrane databases to identify published studies that have evaluated the diagnostic role of the telomerase activity assay for MPE. Sensitivity, specificity and other measures of accuracy of the telomerase activity assay in the diagnosis of MPE were pooled using the random effects models. A summary receiver operating characteristic (SROC) curve was used to summarize overall test performance. A total of eight studies met the inclusion criteria for the meta-analysis. The pooled sensitivity and specificity for diagnosing MPE were 0.76 [95% confidence intervals (CI), 0.72–0.80] and 0.87 (95% CI, 0.83–0.91), respectively. The positive likelihood ratio was 5.19 (95% CI, 2.36–11.42), the negative likelihood ratio was 0.25 (95% CI, 0.11–0.53) and the diagnostic odds ratio was 23.18 (95% CI, 6.11–87.83). The area under the SROC curve was 0.92. The telomerase activity assay plays a role in the diagnosis of MPE with a relatively high specificity. The results of a telomerase activity assay should be interpreted together with the combination of other test results and clinical findings.
malignant pleural effusion; telomerase; meta-analysis
To explore the utility of multidisciplinary approaches in the treatment of patients with pancreatic cancer with liver metastases (PCLM).
From 2002 to 2007, a total of 164 consecutive patients with PCLM treated with chemotherapy, radiation therapy, and/or Chinese herbal medicine (CHM) were included in this study. Clinical parameters, treatments received and survival time from initial diagnosis were analyzed.
Of the 164 patients, 113 (69%) were men and 51 (31%) were women, with median age of 58 years. One hundred and thirty-two patients (80%) had synchronous liver metastases, and 57 patients (35%) had extrahepatic metastases. Overall median survival time of the 164 patients was 4.7 months, 23 (14%) were alive at least 12 months after initial diagnosis of liver metastases. Karnofsky performance status (KPS) <80, weight loss (>10% within 6 months), ascites, and carbohydrate antigen (CA) 19-9 ≥1000 U/mL were the most relevant predictors of poor survival. Multivariate analysis showed that chemotherapy and CHM were protective factors.
Multimodality treatment is well tolerated by patients with PCLM and may be effective in prolonging their survival. Awareness of the implications of these prognostic factors may assist in evaluating the survival potential of patients and selecting the most appropriate treatments.
pancreatic cancer; liver metastases; multimodality treatment; prognosis
In the genome of Thermoanaerobacter tengcongensis, three genes belonging to ROK (Repressor, ORF, and Kinase) family are annotated as glucokinases (GLKs). Using enzyme assays, the three GLKs were identified as ATP-dependent GLK (ATP-GLK), ADP-dependent GLK (ADP-GLK), and N-acetyl-glucosamine/mannosamine kinase (glu/man-NacK). The kinetic properties of the three GLKs such as Km, Vmax, optimal pH, and temperature were characterized, demonstrating that these enzymes performed the specific functions against varied substrates and under different temperatures. The abundance of ATP-GLK was attenuated when culture temperature was elevated and was almost undetectable at 80°C, whereas the ADP-GLK abundance was insensitive to temperature changes. Using degradation assays, ATP-GLK was found to have significantly faster degradation than ADP-GLK at 80°C. Co-immunoprecipitation results revealed that heat shock protein 60 (HSP60) could interact with ATP-GLK and ADP-GLK at 60 and 75°C, whereas at 80°C, the interaction was only effectively with ADP-GLK but not ATP-GLK. The functions of GLKs in T. tengcongensis are temperature dependent, likely regulated through interactions with HSP60.
To study neonatal outcomes in early preterm births by delivery route
Delivery precursors were analyzed in 4,352 singleton deliveries, 24 0/7–31 6/7 weeks’ gestation. In a subset (N=2,906) eligible for a trial of labor, neonatal mortality in attempted vaginal delivery (VD) was compared to planned cesarean delivery (CD) stratified by presentation.
Delivery precursors were classified as maternal or fetal conditions (45.7%), PPROM (37.7%) and preterm labor (16.6%). For vertex presentation, 79% attempted VD and 84% were successful. There was no difference in neonatal mortality. For breech presentation, at 24 0/7 – 27 6/7 weeks’ gestation, 31.7% attempted VD and 27.6% were successful; neonatal mortality was increased (25.2% versus 13.2%, p=0.003). At 28 0/7 – 31 6/7 weeks’ gestation, 30.5% attempted VD and 17.2% were successful; neonatal mortality was increased (6.0% vs. 1.5%, P= 0.016).
Attempted VD for vertex presentation has a high success rate with no difference in neonatal mortality unlike breech presentation.
early preterm birth; precursors; route of delivery
We report here the complete genome sequence of a duck hepatitis A virus 1 (DHAV-1), strain FJ1220, isolated from a dead pigeon in eastern China. DHAV-1 FJ1220 has high homology of up to 99.6% to the DHAV-1 strain Du/CH/LGD/111238 but relatively low homology to strains FFZ05 and FZ05. An amino acid hypervariable region in the VP1 protein of FJ1220 has the motif 180TPSGR184 replaced by 180ALSRG184 compared to strains FFZ05 and FZ05.
We assessed the impact of free on-site influenza vaccination on childcare staff vaccination prevalence using 2 before-and-after studies. Vaccination was offered during the 2003–2004 and 2006–2007 influenza seasons. Staff vaccination prevalence was higher in each intervention season compared to the prior, nonintervention season. No baseline characteristics were associated with receipt of vaccination.
Japanese encephalitis virus (JEV) non-structural protein 1 (NS1) contributes to virus replication and elicits protective immune responses during infection. JEV NS1-specific antibody responses could be a target in the differential diagnosis of different flavivirus infections. However, the epitopes on JEV NS1 are poorly characterized. The present study describes the full mapping of linear B-cell epitopes in JEV NS1. We generated eleven NS1-specific monoclonal antibodies from mice immunized with recombinant NS1. For epitope mapping of monoclonal antibodies, a set of 51 partially-overlapping peptides covering the entire NS1 protein were expressed with a GST-tag and then screened using monoclonal antibodies. Through enzyme-linked immunosorbent assay (ELISA), five linear epitope-containing peptides were identified. By sequentially removing amino acid residues from the carboxy and amino terminal of peptides, the minimal units of the five linear epitopes were identified and confirmed using monoclonal antibodies. Five linear epitopes are located in amino acids residues 5AIDITRK11, 72RDELNVL78, 251KSKHNRREGY260, 269DENGIVLD276, and 341DETTLVRS348. Furthermore, it was found that the epitopes are highly conserved among JEV strains through sequence alignment. Notably, none of the homologous regions on NS1 proteins from other flaviviruses reacted with the MAbs when they were tested for cross-reactivity, and all five epitope peptides were not recognized by sera against West Nile virus or Dengue virus. These novel virus-specific linear B-cell epitopes of JEV NS1 would benefit the development of new vaccines and diagnostic assays.
The effect of heavy metals at environmentally relevant concentrations on couple fecundity has received limited study despite ubiquitous exposure. In 2005–2009, couples (n=501) desiring pregnancy and discontinuing contraception were recruited and asked to complete interviews and to provide blood specimens for the quantification of cadmium (μg/L), lead (μg/dL) and mercury (μg/L) using inductively coupled plasma-mass spectrometry. Couples completed daily journals on lifestyle and intercourse along with menstruation and pregnancy testing for women. Couples were followed for 12 months or until pregnant. Fecundability odds ratios (FORs) and 95% confidence intervals (CIs) were estimated adjusting for age, body mass index, cotinine, and serum lipids in relation to female then male exposures. FORs <1 denote a longer time to pregnancy. In adjusted models, reduced FORs were observed for both female cadmium (0.78; 95% CI 0.63–0.97) and male lead (0.85; 95% CI 0.73–0.98) concentrations. When jointly modeling couples’ exposures, only male lead concentration significantly reduced the FOR (0.82; 95% CI 0.68, 0.97), though the FOR remained <1 for female cadmium (0.80; 95% CI 0.64, 1.00). This prospective couple based cohort with longitudinal capture of time to pregnancy is suggestive of cadmium and lead’s reproductive toxicity at environmentally relevant concentrations.
cadmium; fecundity; lead; mercury; reproduction; time-to-pregnancy
To examine the effects and safety of high-dose (compared with low-dose) oxytocin regimen for labor augmentation on perinatal outcomes.
Data from the Consortium on Safe Labor were used. A total of 15,054 women from six hospitals were eligible for the analysis. Women were grouped based on their oxytocin starting dose and incremental dosing: 1, 2, and 4 mU/min. Duration of labor and a number of maternal and neonatal outcomes were compared among these three groups stratified by parity. Multivariable logistic regression and generalized linear mixed model were used to adjust for potential confounders.
Oxytocin regimen did not affect the rate of cesarean delivery or other perinatal outcomes. Compared to 1 mU/min, the regimens starting with 2 mU/min and 4 mU/min reduced the duration of 1st stage by 0.8 hours (95% confidence interval 0.5 – 1.1) and 1.3 hours (1.0 – 1.7), respectively, in nulliparas. No effect was observed on the second stage of labor. Similar patterns were observed in multiparas. High-dose regimen was associated with a reduced risk of meconium stain, chorioamnionitis, and newborn fever in multiparas.
High-dose oxytocin regimen (starting dose at 4 mU/min and increment of 4 mU/min) is associated with a shorter duration of first stage of labor in all parities without increasing the cesarean delivery rate or adversely affecting perinatal outcomes.
Benzophenone (BP)-type ultraviolet (UV) filters are widely used in a variety of personal care products for the protection of skin and hair from UV irradiation. Despite the estrogenic potencies of BP derivatives, few studies have examined the occurrence of these compounds in human matrices. Furthermore, associations among exposure to these compounds and estrogen-dependent diseases (such as endometriosis) have not been examined previously. In this study, we determined the concentrations of five BP derivatives, 2-hydroxy-4-methoxybenzophenone (2OH-4MeO-BP), 2,4-dihydroxybenzophenone (2,4OH-BP), 2,2’-dihydroxy-4-methoxybenzophenone (2,2’OH-4MeO-BP), 2,2’,4,4’-tetrahydroxybenzophenone (2,2’,4,4’OH-BP) and 4-hydroxybenzophenone (4OH-BP), in urine collected from 625 women in Utah and California, using liquid chromatography (LC)-tandem mass spectrometry (MS/MS). The association of urinary concentrations of BP derivatives with an increase in the odds of a diagnosis of endometriosis was examined in 600 women who underwent laparoscopy/laparotomy (n = 473: operative cohort) or pelvic magnetic resonance imaging (n = 127: population cohort), during 2007-2009. 2OH-4MeO-BP, 2,4OH-BP, and 4OH-BP, respectively, were detected in 99.0%, 93.3%, and 83.8% of the urine samples analyzed, whereas the detection rates for 2,2’,4,4’OH-BP and 2,2’OH-4MeO-BP were below 6.0%. Significant regional differences (higher concentrations in California) and monthly variations (higher concentrations in July and August) were found for urinary concentrations of 2OH-4Me O-BP and 2,4OH-BP. In addition, urinary concentrations of 2OH-4MeO-BP and 2,4OH-BP tended to be higher in more affluent, older, and leaner women. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the urinary concentrations of BP derivatives and the odds of an endometriosis diagnosis; ORs increased across quartiles of 2OH-4MeO-BP and 2,4OH-BP concentrations, but a significant trend was observed only between 2,4OH-BP and the odds of an endometriosis diagnosis in the operative cohort (OR = 1.19; 95% CI = 1.01, 1.41). When women in the highest quartile of 2,4OH-BP concentrations were compared with women in the first three quartiles, the OR increased considerably (AOR = 1.65; 95% CI = 1.07, 2.53). Given that 2,4OH-BP possesses an estrogenic activity higher than that of 2OH-4MeO-BP, our results invite the speculation that exposure to elevated 2,4OH-BP levels may be associated with endometriosis.
Benzophenone derivatives; UV filters; sunscreen agents; estrogenic activity; endometriosis; epidemiology
Starting from the active ingredient shikimic acid (SA) of traditional Chinese medicine and NH2(CH2)nOH, (n = 2–6), we have synthesized a series of new water-soluble Pt(II) complexes PtLa–eCl2, where La–e are chelating diamine ligands with carbon chain covalently attached to SA (La–e = SA-NH(CH2)nNHCH2CH2NH2; La, n = 2; Lb, n = 3; Lc, n = 4; Ld, n = 5; Le, n = 6). The results of the elemental analysis, LC-MS, capillary electrophoresis, and 1H, 13C NMR indicated that there was only one product (isomer) formed under the present experimental conditions, in which the coordinate mode of PtLa–eCl2 was two-amine bidentate. Their in vitro cytotoxic activities were evaluated by MTT method, where these compounds only exhibited low cytotoxicity towards BEL7404, which should correlate their low lipophilicity. The interactions of the five Pt(II) complexes with DNA were investigated by agarose gel electrophoresis, which suggests that the Pt(II) complexes could induce DNA alteration. We also studied the interactions of the Pt(II) complexes with 5′-GMP with ESI-MS and 1H NMR and found that PtLbCl2, PtLcCl2, and PtLdCl2 could react with 5′-GMP to form mono-GMP and bis-GMP adducts. Furthermore, the cell-cycle analysis revealed that PtLbCl2, PtLcCl2 cause cell G2-phase arrest after incubation for 72 h. Overall, these water-soluble Pt(II) complexes interact with DNA mainly through covalent binding, which blocks the DNA synthesis and replication and thus induces cytotoxicity that weakens as the length of carbon chain increases.
Despite a general repression of translation under hypoxia, cells selectively upregulate a set of hypoxia-inducible genes. Results from deep sequencing revealed that Let-7 and miR-103/107 are hypoxia-responsive microRNAs (HRMs) that are strongly induced in vascular endothelial cells. In silico bioinformatics and in vitro validation showed that these HRMs are induced by HIF1α and target argonaute 1 (AGO1), which anchors the microRNA-induced silencing complex (miRISC). HRM targeting of AGO1 resulted in the translational desuppression of VEGF mRNA. Inhibition of HRM or overexpression of AGO1 without the 3′ untranslated region decreased hypoxia-induced angiogenesis. Conversely, AGO1 knockdown increased angiogenesis under normoxia in vivo. In addition, data from tumor xenografts and human cancer specimens indicate that AGO1-mediated translational desuppression of VEGF may be associated with tumor angiogenesis and poor prognosis. These findings provide evidence for an angiogenic pathway involving HRMs that target AGO1 and suggest that this pathway may be a suitable target for anti- or proangiogenesis strategies.
Aims: The role of endothelium-derived contracting factors (EDCFs) in regulating renovascular function is yet to be elucidated in renovascular hypertension (RH). The current study investigated whether oxidative stress-dependent cyclooxygenase (COX)-2-derived prostaglandin F2α (PGF2α) impairs endothelial function in renal arteries of renovascular hypertensive rats (RHR). Results: Renal hypertension was induced in rats by renal artery stenosis of both kidneys using the 2-kidney 2-clip model. Acute treatment with reactive oxygen species (ROS) scavengers, COX-2 inhibitors, and thromboxane-prostanoid receptor antagonists, but not COX-1 inhibitors, improved endothelium-dependent relaxations and eliminated endothelium-dependent contractions in RHR renal arteries. Five weeks of treatment with celecoxib or tempol reduced blood pressure, increased renal blood flow, and restored endothelial function in RHRs. Increased ROS production in RHR arteries was inhibited by ROS scavengers, but unaffected by COX-2 inhibitors; whereas increased PGF2α release was reduced by both ROS scavengers and COX-2 inhibitors. ROS also induced COX-2-dependent contraction in RHR renal arteries, which was accompanied by the release of COX-2-derived PGF2α. Further, chronic tempol treatment reduced COX-2 and BMP4 upregulation, p38MAPK phosphorylation, and the nitrotyrosine level in RHR renal arteries. Conclusion: These findings demonstrate the functional importance of oxidative stress, which serves as an initiator of increased COX-2 activity, and that COX-2-derived PGF2α plays an important role in mediating endothelial dysfunction in RH. Innovation: The current study, thus, suggests that drugs targeting oxidative stress-dependent COX-2-derived PGF2α may be useful in the prevention and management of RH. Antioxid. Redox Signal. 16, 363–373.
Background: Evidence suggesting that persistent environmental pollutants may be reproductive toxicants underscores the need for prospective studies of couples for whom exposures are measured.
Objectives: We examined the relationship between selected persistent pollutants and couple fecundity as measured by time to pregnancy.
Methods: A cohort of 501 couples who discontinued contraception to become pregnant was prospectively followed for 12 months of trying to conceive or until a human chorionic gonadotrophin (hCG) test confirmed pregnancy. Couples completed daily journals on lifestyle and provided biospecimens for the quantification of 9 organochlorine pesticides, 1 polybrominated biphenyl, 10 polybrominated diphenyl ethers, 36 polychlorinated biphenyls (PCBs), and 7 perfluorochemicals (PFCs) in serum. Using Cox models for discrete time, we estimated fecundability odds ratios (FORs) and 95% CIs separately for each partner’s concentrations adjusting for age, body mass index, serum cotinine, serum lipids (except for PFCs), and study site (Michigan or Texas); sensitivity models were further adjusted for left truncation or time off of contraception (≤ 2 months) before enrollment.
Results: The adjusted reduction in fecundability associated with standard deviation increases in log-transformed serum concentrations ranged between 18% and 21% for PCB congeners 118, 167, 209, and perfluorooctane sulfonamide in females; and between 17% and 29% for p,p´-DDE and PCB congeners 138, 156, 157, 167, 170, 172, and 209 in males. The strongest associations were observed for PCB 167 (FOR 0.79; 95% CI: 0.64, 0.97) in females and PCB 138 (FOR = 0.71; 95% CI: 0.52, 0.98) in males.
Conclusions: In this couple-based prospective cohort study with preconception enrollment and quantification of exposures in both female and male partners, we observed that a subset of persistent environmental chemicals were associated with reduced fecundity.
conception; cotinine; fecundity; organochlorine pesticides; polybrominated diphenyl ethers; polychlorinated biphenyls; perfluorochemicals; time to pregnancy
High-dimensional biomarker data are often collected in epidemiological studies when assessing the association between biomarkers and human disease is of interest. We develop a latent class modeling approach for joint analysis of high-dimensional semicontinuous biomarker data and a binary disease outcome. To model the relationship between complex biomarker expression patterns and disease risk, we use latent risk classes to link the 2 modeling components. We characterize complex biomarker-specific differences through biomarker-specific random effects, so that different biomarkers can have different baseline (low-risk) values as well as different between-class differences. The proposed approach also accommodates data features that are common in environmental toxicology and other biomarker exposure data, including a large number of biomarkers, numerous zero values, and complex mean–variance relationship in the biomarkers levels. A Monte Carlo EM (MCEM) algorithm is proposed for parameter estimation. Both the MCEM algorithm and model selection procedures are shown to work well in simulations and applications. In applying the proposed approach to an epidemiological study that examined the relationship between environmental polychlorinated biphenyl (PCB) exposure and the risk of endometriosis, we identified a highly significant overall effect of PCB concentrations on the risk of endometriosis.
Categorical data; Chemical exposure biomarkers; Latent variables; Monte Carlo EM algorithm; Random effects