Text mining for improved exposure assessment

Chemical exposure assessments are based on information collected via different methods, such as biomonitoring, personal monitoring, environmental monitoring and questionnaires. The vast amount of chemical-specific exposure information available from web-based databases, such as PubMed, is undoubtedly a great asset to the scientific community. However, manual retrieval of relevant published information is an extremely time consuming task and overviewing the data is nearly impossible. Here, we present the development of an automatic classifier for chemical exposure information. First, nearly 3700 abstracts were manually annotated by an expert in exposure sciences according to a taxonomy exclusively created for exposure information. Natural Language Processing (NLP) techniques were used to extract semantic and syntactic features relevant to chemical exposure text. Using these features, we trained a supervised machine learning algorithm to automatically classify PubMed abstracts according to the exposure taxonomy. The resulting classifier demonstrates good performance in the intrinsic evaluation. We also show that the classifier improves information retrieval of chemical exposure data compared to keyword-based PubMed searches. Case studies demonstrate that the classifier can be used to assist researchers by facilitating information retrieval and classification, enabling data gap recognition and overviewing available scientific literature using chemical-specific publication profiles. Finally, we identify challenges to be addressed in future development of the system.S.B. received funding from Commonwealth Scholarship Commission (http://cscuk.dfid.gov.uk/), Cambridge Trust (https://www.cambridgetrust.org/). A.K. received funding from Medical Research Council UK grant MR/M013049/1

Detection of sexually transmitted infection and human papillomavirus in negative cytology by multiplex-PCR

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to determine the prevalence of human papillomavirus (HPV) and 15 species that cause sexually transmitted infections (STIs) in negative cytology. In addition, we compared the diagnostic performance of multiplex polymerase chain reaction (PCR) with widely available techniques used to detect HPV.</p> <p>Methods</p> <p>We recruited 235 women of reproductive age who had negative cytology findings in a liquid-based cervical smear. STIs were identified by multiplex PCR, and HPV genotypes by multiplex PCR, hybrid capture 2, and DNA microaray; discordant results were analyzed by direct sequencing.</p> <p>Results</p> <p>Approximately 96.6% of patients with negative cytology results were positive for pathogens that cause STIs. The pathogens most frequently detected were <it>Gardnerella vaginalis, Ureaplasma urealyticum</it>. The incidence of HPV in negative cytology was 23.3%. Low-risk HPV infection was significantly correlated with <it>Chalmaydia trachomatis</it>, and high-risk HPV infection was significantly correlated with <it>Group β streptococcus</it>. The analytical sensitivities of the multiplex PCR and DNA microarray were higher than 80%, and the analytical specificity was nearly 100% for all tests.</p> <p>Conclusions</p> <p>Multiplex PCR yielded results that most of patients with negative cytology were positive for pathogens that cause STIs, and were more similar to that of DNA microarray, than that of hybrid capture 2 in terms of analytical sensitivity and prediction value of HPV infection.</p

PARP-1 Val762Ala Polymorphism Is Associated with Risk of Cervical Carcinoma

PARP-1 is a nuclear enzyme that plays an important role in DNA repair, recombination, proliferation and the genome stability. The PARP-1 Val762Ala polymorphism has been associated with increased risk of developing cancers of the prostate, esophagus and lung. The aim of this study was to determine whether the PARP-1 Val762Ala polymorphism is associated with the risk of cervical carcinoma. MA-PCR was used to genotype the PARP-1 Val762Ala polymorphism in 539 women with cervical carcinoma, 480 women with CIN and 800 controls. The genotyping method was confirmed by the DNA sequencing analysis. The PARP-1 Val762Ala polymorphism was not associated with the risk of CIN. However, women carrying the PARP-1 Ala762Ala genotype were significantly susceptible to cervical carcinoma (OR: 2.70, 95% CI: 1.47–3.70), and the similar results were also found in squamous cell carcinoma (OR: 2.56, 95% CI: 1.47–3.70). In HPV positive population, the PARP-1 Ala762Ala genotype was also associated with increased risk of cervical carcinoma (OR: 5.56, 95% CI: 2.08–14.3). Our results indicate that the PARP-1 Ala762Ala genotype increases the risk of cervical carcinoma

Assessing Perceived Risk and STI Prevention Behavior: A National Population-Based Study with Special Reference to HPV

Aim: This thesis aims to provide a multidimensional assessment of infection risks and to evaluate strategies for HPV prevention including vaccination with quadrivalent HPVvaccines, dose-level vaccine effectiveness and condom use in high STI risk situations. Methods: Multiple population-based registers and questionnaire responses provided data for this thesis. Various multivariable and univariate regression models were fit. Findings: Overall, quadrivalent HPV-vaccination was highly effective against genital warts (GW) also referred to as condyloma, which is the first HPV disease endpoint possible to measure. However, effectiveness was contingent upon young age-at-first vaccination, with effectiveness declining steadily the older the age-at-first vaccination. Among women above 20 years of age there was low to immeasurable effectiveness and suggestive evidence vaccinations in this age group tended to reach women at high GW risk. There were marked socioeconomic disparities in the opportunistic (on-demand with co-pay) vaccination strategy evaluated, with women and girls who have parents with the highest education level compared to the lowest having a 15 times greater likelihood to be vaccinated (Study III). Once vaccination was initiated, however, high parental education level was unrelated to vaccination completion. Maximum protection against GW was found among girls vaccinated under the age of 17 who had received three doses of the vaccine. No differences in effectiveness were found for girls who received twodoses between ages 10-16 with that of those who received three-doses between ages 17- 19 (Study IV). GW affects more men than women in Sweden as of 2010 with 453 per 100 000 men and 365 per 100 000 women treated. A decline between 25-30% was seen between 2006 and 2010 among women in the age groups with the highest vaccination coverage. No decline was found amongst men and their GW incidence has steadily increased between 2006 and 2010 (Study II). Reported condom use in high risk situations was low among both men and women, with 41% of men and 34% of women reporting always/almost always condom use with temporary partners. STI risk perception was also low, with approximately 10% of sexually active respondents considering themselves at large risk of contracting an STI. There was no association between men’s condom use and their STI risk perception but there was an association for women (Study I). Conclusions: Results suggest that males bear a substantial burden of HPV-related condyloma where incidence has dropped among women. When planning HPVvaccination among females, efforts should target girls under age 14 for maximum effectiveness. Quadrivalent HPV-vaccination offers most protection against condyloma at three doses. Gross social inequity was found with opportunistic HPV-vaccination. There were large gender differences in factors associated with condom use in high risk situations and STI risk perceptions

A prospective study of the relationship between prediagnostic Human Papillomavirus seropositivity and HPV DNA in subsequent cervical carcinomas

Several prospective studies with invasive carcinoma as endpoint have supported Human Papillomavirus as a cause of cervical carcinoma. However, the largest study used seroepidemiology and did not analyse presence of Human Papillomavirus DNA in the subsequent tumour. Linkage of serum bank registries and cancer registries had identified 196 women with a registered cervical carcinoma after donation of a serum sample. For the present study, biopsies for 127 cases could be located, verified to contain invasive carcinoma and be amplified by PCR. Three control women who had remained alive and without cervical carcinoma during an equal length of follow-up had been matched to each of the case women and tested for HPV antibodies. Presence of Human Papillomavirus DNA in the tumours was analysed by general primer and type specific PCR. HPV16-seropositive women had a relative risk of 4.4 (95% CI: 2.2–8.8) to develop cervical carcinoma carrying HPV16 DNA. By contrast, there was no excess risk for Human Papillomavirus 16-seropositive women to develop cervical carcinoma devoid of HPV16 DNA. Prediagnostic HPV16 seropositivity was strongly correlated with later HPV16 DNA positivity of the tumour (P<0.001) and prediagnostic HPV18 seropositivity correlated with HPV18 DNA in the tumour (P<0.03). The link between prediagnostic seropositivity and type of viral DNA in the cancer implies that the carcinogenic effect of infection with these viruses is dependent on persistent presence of type-specific viral DNA

Population-based type-specific prevalence of high-risk human papillomavirus infection in Estonia

<p>Abstract</p> <p>Background</p> <p>Effective prophylactic vaccines are available against human papillomavirus (HPV) types 6, 11, 16, and 18 which are licensed for routine use among young women. Monitoring is needed to demonstrate protection against cervical cancer, to verify duration of protection, and assess replacement frequency of non-vaccine types among vaccinated cohorts.</p> <p>Methods</p> <p>Data from a population-based study were used to assess the type-specific prevalence of HPV in a non-vaccinated population in Estonia: 845 self-administered surveys and self-collected vaginal swabs were distributed, 346 were collected by mail and tested for HPV DNA from female participants 18-35 years of age.</p> <p>Results</p> <p>The overall HPV prevalence (weighted estimate to account for the sampling method) in the study population (unvaccinated women aged 18-35) was calculated to be 38% (95% CI 31-45%), with estimated prevalences of high- and low-risk HPV types 21% (95% CI 16-26%), and 10% (95% CI 7-14%), respectively. Of the high-risk HPV types, HPV 16 was detected most frequently (6.4%; 95% CI 4.0-9.8%) followed by HPV 53 (4.3%; 95% CI 2.3-7.2%) and HPV 66 (2.8%; 95% CI 1.3-5.2%).</p> <p>Conclusions</p> <p>We observed a high prevalence of total and high-risk type HPV in an Eastern European country. The most common high-risk HPV types detected were HPV 16, 53, and 66.</p

Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis

Alkaline sphingomyelinase (alk-SMase) is expressed in the intestine and human liver. It may inhibit colonic tumorigenesis, and loss of function mutations have been identified in human colon cancer. The present study investigates its expression in human liver cancer. In HepG2 liver cancer cells, RT–PCR identified three transcripts with 1.4, 1.2 and 0.4 kb, respectively. The 1.4 kb form is the wild-type cDNA with five translated exons, the 1.2 kb product lacks exon 4 and the 0.4 kb form is a combination of exons 1 and 5. Genomic sequence showed that these aberrant transcripts were products of alternative splicing. Transient expression of the 1.2 kb form showed no alk-SMase activity. In HepG2 cells, the alk-SMase activity is low in monolayer condition and increased with cell polarisation. Coexistence of 1.4 and 1.2 kb forms was also identified in one hepatoma biopsy. GenBank search identified a cDNA clone from human liver tumour, which codes a protein containing full length of alk-SMase plus a 73-amino-acid tag at the N terminus. The aberrant form was translated by an alternative starting codon upstream of the wild-type mRNA. Expression study showed that linking the tag markedly reduced the enzyme activity. We also analysed human liver biopsy samples and found relatively low alk-SMase activity in diseases with increased risk of liver tumorigenesis. In conclusion, expression of alk-SMase is changed in hepatic tumorigenesis, resulting in loss or marked reduction of the enzyme function

CREB Inhibits AP-2α Expression to Regulate the Malignant Phenotype of Melanoma

The loss of AP-2alpha and increased activity of cAMP-responsive element binding (CREB) protein are two hallmarks of malignant progression of cutaneous melanoma. However, the molecular mechanism responsible for the loss of AP-2alpha during melanoma progression remains unknown.Herein, we demonstrate that both inhibition of PKA-dependent CREB phosphorylation, as well as silencing of CREB expression by shRNA, restored AP-2alpha protein expression in two metastatic melanoma cell lines. Moreover, rescue of CREB expression in CREB-silenced cell lines downregulates expression of AP-2alpha. Loss of AP-2alpha expression in metastatic melanoma occurs via a dual mechanism involving binding of CREB to the AP-2alpha promoter and CREB-induced overexpression of another oncogenic transcription factor, E2F-1. Upregulation of AP-2alpha expression following CREB silencing increases endogenous p21(Waf1) and decreases MCAM/MUC18, both known to be downstream target genes of AP-2alpha involved in melanoma progression.Since AP-2alpha regulates several genes associated with the metastatic potential of melanoma including c-KIT, VEGF, PAR-1, MCAM/MUC18, and p21(Waf1), our data identified CREB as a major regulator of the malignant melanoma phenotype

Human papillomavirus in high- and low-risk areas of oesophageal squamous cell carcinoma in China

To examine the potential roles of human papillomavirus (HPV) in oesophageal squamous cell carcinoma (ESCC) development, we examined the presence of HPV DNA in paraffin-embedded ESCC tissues collected from two areas with different ESCC incidence rates in China, that is, Gansu (n=26) and Shandong (n=33), using PCR with SPF10 primers, or PCR with GP5+/GP6+ primers combined with Southern blot hybridisation. HPV genotype was determined by the INNO-LiPA HPV genotyping kit. HPV DNA was detected in 17 cases (65%) in Gansu, where ESCC incidence is much higher than in Shandong, where HPV was positive in two samples (6%). HPV genotypes 16 and 18 were detected in 79 and 16% of HPV-positive samples, respectively. Real-time PCR analysis suggested the presence of integrated form of HPV DNA in all the HPV-16-positive samples, but its viral load was estimated to be only <1–2 copies cell−1. We could not detect HPV 16/18 E6 protein expression by immunostaining in any of the HPV-16-positive samples. Neither p16INK4a nor p53 expression was related to HPV presence in ESCCs. Further studies seem warranted to examine the possible aetiological roles of HPV in ESCC