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Background: This is the era of the elderly. In India, there is an exponential increase in the aging population. Increase in longevity means that the community will have to bear a greater burden of disease. The general health and well-being of older adults are related to their oral health. Aim: The to study the perceived barriers and attitudes of undergraduate dental students towards geriatric dental care. Materials and Methods: Four hundred and eighty senior dental students participated in the present cross-sectional questionnaire study. The first sought background information including gender, age, prior treating in geriatric dental care, and prior experience in treating the elderly in their education. The responses were categorized in a Likert scale. Data were analyzed using SPSS version 20. P < 0.05 was considered as statistically significant. Fisher exact test was used to know the attitude to work with elderly and the barriers in elderly dental care. Gender-wise comparison of mean attitude score toward the elderly was done. Results: The perceived barriers of dental students' showed significant association with respect to financial ability of the elderly (P = 0.017), follow-up of elderly patients (P = 0.04), elderly patient compliance (P = 0.05), and inadequate communication skills in treating elderly patients (P = 0.05). Females (2.500 ± 0.48) showed positive attitude when compared to male (1.166 ± 0.19) study subjects. The total attitudes mean score was 1.87 ± 0.34. Conclusions: Even though dental students were willing for elderly dental care, student's inadequate knowledge of geriatric care, poor communication skills, and lack of confidence in management of elderly patients are the identified barriers.

Introduction: Poor oral health in systemically diseased individuals besides worsening the glycaemic status also has functional, social consequences such as masticatory inefficiency and stigmatized social participation, respectively. Periodontal problems remain one of the most common reasons for tooth mortality along with tooth decay and trauma., Methodology: The study was conducted in the outpatient department of teaching dental institution among the individuals visiting the institution. Persons with systemic illness were included in the study. In the preliminary step, interviews were conducted among the study participants regarding health status followed by an oral health examination. The oral health examination included recording of community periodontal index and dentition status. Data were collected and statistical analyses were performed. Chi-square test, one-way ANOVA and Bonferroni post-hoc tests were used to analyze the data., Results: Patients with diabetes showed the highest (3.56 ± 2.98) number of missing teeth, followed by other systemic diseases (2.78 ± 2.74), and the patients who were not having any systemic diseases (1.81 ± 1.54). This distinction was found to be statistically significant ( P = 0.001), and Bonferroni post-hoc shows statistical significance ( P < 0.05) in group-wise comparisons. The number of teeth last due to caries among diabetics was higher (20.8%) when compared to nondiabetic (12.2%), and the most tooth loss due to periodontitis was also observed within the patients with diabetes (21%) when compared to patients with other systemic diseases (12%), which is statistically significant ( P = 0.001)., Conclusion: The current study revealed tooth loss is more common in the patients who have systemic diseases when compared to the patients who do not have any systemic diseases, while dental caries and periodontal problems are the principle causes of tooth mortality., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

Introduction: As coronavirus disease 2019 (COVID-19) is a new disease which has ruining and dismantling the harmony of people internationally, its development and spread, creates turmoil, nervousness and dread among worldwide., Aim: To evaluate seriousness of peritraumatic problems among southern Indian inhabitants during the COVID-19 pandemic., Methodology: A referral sampling technique was continued until a sufficient sample size was reached, while this self-administered survey catches insights about depression, fears, psychological change, evasion cognitive change, and collectively quantifies the stress on a scale of 0-60. Expressive factual examinations were utilized to sum up clear cut information and inferential measurable investigations included Chi-square tests and Pearson's correlations were done., Results: The study included only those participants who understood English and had access to the internet. Inconsequential outcomes were found among gender in which both male and female members frequently showed apprehension and nervousness about COVID-19. 44.8% tried not to watch the news on COVID-19 as they were excessively frightened and make frenzy to family members. 90.9% of participants with lower education levels were more stressed over the thought of getting COVID-19 when showing manifestations related with the novel corona virus, which was statistically significant., Conclusion: The current assessment shows that almost all the study participants have felt restless, uncomfortable and terrified of watching the news whilst stressed over appearances related with COVID-19 due to their greater access to information., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Family Medicine and Primary Care.)

Background: Reddit, the fifth most popular website in the United States, boasts a large and engaged user base on its dermatology forums where users crowdsource free medical opinions. Unfortunately, much of the advice provided is unvalidated and could lead to the provision of inappropriate care. Initial testing has revealed that artificially intelligent bots can detect misinformation regarding tanning and essential oils on Reddit dermatology forums and may be able to produce responses to posts containing misinformation., Objective: To analyze the ability of bots to find and respond to tanning and essential oil-related health misinformation on Reddit's dermatology forums in a controlled test environment., Methods: Using natural language processing techniques, we trained bots to target misinformation, using relevant keywords and to post prefabricated responses. By evaluating different model architectures across a held-out test set, we compared performances., Results: Our models yielded data test accuracies ranging 95%-100%, with a Bidirectional Encoder Representations from Transformers (BERT) fine-tuned model resulting in the highest level of test accuracy. Bots were then able to post corrective prefabricated responses to misinformation in a test environment., Conclusions: Using a limited data set, bots accurately detected examples of health misinformation within Reddit dermatology forums. Given that these bots can then post prefabricated responses, this technique may allow for interception of misinformation. Providing correct information does not mean that users will be receptive or find such interventions persuasive. Further studies should investigate this strategy's effectiveness to inform future deployment of bots as a technique in combating health misinformation., (©Monique A Sager, Aditya M Kashyap, Mila Tamminga, Sadhana Ravoori, Christopher Callison-Burch, Jules B Lipoff. Originally published in JMIR Dermatology (http://derma.jmir.org), 30.09.2021.)

Introduction: The regard for dentistry as a profession has been declining over the recent years in light of the increasing number of dental students graduating per year with negligible improvement in the utilization of oral health care services. In this context, it is important to document the perceptions and apprehensions of the current dental students as these feelings would have an influence on the roles they assume as dentists in future., Aim: With this background, this study attempts to document the willingness of dental students from three South Indian states to re-choose dentistry given an opportunity., Materials and Methods: This cross-sectional survey was conducted among house surgeons from 12 dental institutions, 4 each from the southern Indian states of Andhra Pradesh, Telangana, and Tamilnadu. The semi-structured questionnaire used in this study consisted of five primary questions along with details on the participants' gender, type of admission. It aimed at documenting the willingness to re-choose dentistry given an opportunity, and the reasons for their willingness or otherwise. A total of 822 students constituted the final sample. SPSS version 20 software was used to analyse the data., Results: Majority of the study participants were from Tamil Nadu, not reported dentistry as their primary career choice, and demonstrated reluctance in re-choosing dentistry given an opportunity. A significantly higher percentage of dental students from Tamil Nadu reported dentistry as their first professional choice. This observation persisted in the response of students for the question on their willingness to re-choose dentistry., Conclusion: The study results demonstrate the declining interest and regard for dentistry among the current dental students with nominal variations between students from the three South Indian states., Competing Interests: None

Purpose: Oral health literacy (OHL) is a relatively unexplored construct in the Indian context. Most of the few previous studies estimating OHL among different populations of India used instruments that were either previously validated in a different country or not tested for psychometric properties. With this background, the objective of this study was to develop an Indian oral health literacy measure and to evaluate the psychometric properties of the instrument among Telugu speaking population of Andhra Pradesh (IOHLM-T)., Materials and Methods: The initial version of the instrument after evaluated for face and content validity was tested for psychometric properties among 200 adult patients visiting the outpatient department of SIBAR Institute of Dental Sciences. Predictive validity of the instrument was checked by the association between IOHLM-T score and oral health impact profile (OHIP-14), decayed-missing-filled teeth (DMFT) scores. Convergent validity was tested by assessing the correlation between IOHLM-T score and rapid estimate of adult literacy in dentistry (REALD-30) score., Statistical Analysis: SPSS version 20 software was used to analyse the data. Independent samples t-test, Pearson's correlation, one-way ANOVA and stepwise multiple linear regression were done to analyse the data., Results: IOHLM-T demonstrated good internal consistency reliability (Cronbach's alpha 0.75), convergent validity (r = 0.34 between Reald-30 and IOHLM-T scores) and predictive validity (significant negative correlation of IOHLM-T with OHIP-14 and DMFT scores)., Conclusion: IOHLM-T demonstrates good face validity, content validity, predictive validity, convergent validity and internal consistency reliability and thus can be used among different populations in India after translation to the corresponding languages and evaluation of psychometric properties., Competing Interests: None

Introduction: In a country where 30,570 dentists graduate per year, it is staggering to acknowledge that only 10% of dentists serve the rural people, who constitute around 68.8% of the country's population., Aim: To find out the oral healthcare-seeking behavior, profile, and pattern in Tenali Mandal among WHO recommended index age groups., Materials and Methods: A cross-sectional, multilocality, single-visit study was done to acknowledge the oral healthcare-seeking behavior, profile, and pattern in Tenali Mandal, Guntur, Andhra Pradesh. There are 9 villages, 2 peri-urban, and 1 town present in the Tenali Mandal and the study was conducted following the National Pathfinder Survey., Results: Around 35.4% of the study participants utilized dental services while most of them sought care in the last 1-6 months (23.4%) and the main reason for the last dental visit was tooth pain (13.1%), followed by decayed tooth without pain (6.9%). Dental care-seeking behavior among the age group of 12 years was 1.611 times more when compared to 65-74 years age group which was statistically significant ( P ≤ 0.010). For dental care-seeking behavior among gender, the males utilized 0.982 times less when compared to females which was not statistically significant ( P ≤ 0.881), while for the place of residence, urban place was 2.707 times more utilizing the services when compared to rural place which was statistically significant ( P ≤ 0.001)., Conclusion: The results of the study indicates that the barriers of oral healthcare-seeking behavior among dental health conditions poses public health problems in the study area, as well as it is an important baseline indicator against which target for oral health improvement can be set and monitored., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Journal of Family Medicine and Primary Care.)

Background: Tobacco use is a major global public health threat for all countries and no form of tobacco use is safe. Pictorial warnings covering 40% area of tobacco products are made mandatory from May 31, 2009 in India. The present study was aimed to investigate the awareness and attitude toward pictorial warnings on tobacco products among age 15 years and above population in field-practice area., Materials and Methods: A total of 1064 individuals were selected by systematic random sampling. A model containing the pictorial warnings were shown to the study subjects, and data were collected by semi-structured questionnaire. Data was analyzed using SPSS 20 and statistical tests used were Chi-square test. Significance level set at P ≤ 0.05., Results: Of the 1064 individuals participated in the study, 53.9% were male and the mean age of the study population was 31.24 ± 5.8. Nearly 45.8% reported using tobacco in some form and all of them were males. 51.3% of both males and females reported that they never came across antitobacco messages (pictorial warnings). 71.2% believed that the size and position of pictorial warnings on tobacco products were not sufficient to understand the harmful effects of tobacco. There was statistically significant difference between different age groups in their responses to the aforementioned questions., Conclusion: The results of present study demonstrate that the need for pictorial warnings on tobacco products to be more clear and explanatory since there is little point in having pictorial warnings when the prime purpose of having them is not being served., Competing Interests: There are no conflicts of interest.

Scientific evidence suggests that many herbs and spices have medicinal properties that alleviate symptoms or prevent disease. In this study, we examined the chemopreventive effects of the Apiaceae spices, anise, caraway, and celery seeds against 17β-estrogen (E2)-mediated mammary tumorigenesis in an ACI (August-Copenhagen Irish) rat model. Female ACI rats were given either control diet (AIN 93M) or diet supplemented with 7.5% ( w / w ) of anise, caraway, or celery seed powder. Two weeks later, one half of the animals in each group received subcutaneous silastic implants of E2. Diet intake and body weight were recorded weekly, and animals were euthanized after 3 and 12 weeks. E2-treatment showed significantly (2.1- and 3.4-fold) enhanced growth of pituitary gland at 3 and 12 weeks, respectively. All test spices significantly offset the pituitary growth by 12 weeks, except celery which was effective as early as three weeks. Immunohistochemical analysis for proliferative cell nuclear antigen (PCNA) in mammary tissues showed significant reduction in E2-mediated mammary cell proliferation. Test spices reduced the circulating levels of both E2 and prolactin at three weeks. This protection was more pronounced at 12 weeks, with celery eliciting the highest effect. RT-PCR and western blot analysis were performed to determine the potential molecular targets of the spices. Anise and caraway diets significantly offset estrogen-mediated overexpression of both cyclin D1 and estrogen receptor α (ERα). The effect of anise was modest. Likewise, expression of CYP1B1 and CYP1A1 was inhibited by all test spices. Based on short-term molecular markers, caraway was selected over other spices based on its enhanced effect on estrogen-associated pathway. Therefore, a tumor-end point study in ACI rats was conducted with dietary caraway. Tumor palpation from 12 weeks onwards revealed tumor latency of 29 days in caraway-treated animals compared with first tumor appearance at 92 days in control group. At the end of the study (25 weeks), the tumor incidence was 96% in the control group compared with only 70% in the caraway group. A significant reduction in tumor volume (661 ± 123 vs. 313 ± 81 mm³) and tumor multiplicity (4.2 ± 0.4 vs. 2.5 ± 0.5 tumors/animal) was also observed in the caraway group compared with the control group. Together, our data show dietary caraway can significantly delay and prevent the hormonal mammary tumorigenesis by modulating different cellular and molecular targets.

Introduction: The biological process of ageing is outside human control and has its own dynamics. It is a known fact that elderly people have more treatment needs compared to the younger population and at the same time elderly people are facing a multitude of barriers in utilization of health care as well as oral health care., Aim: To identify the utilization patterns of oral health care and barriers for utilization among rural population., Materials and Methods: A cross-sectional study was done on 621 rural elderly subjects to identify the utilization of oral health care services and the barriers for utilization. Using stratified cluster sampling study area was stratified into 13 rural clusters, fifty houses were randomly selected from each stratum. All the elderly subjects, as defined by the age criteria were considered for study. The data were analysed using SPSS 20 v and Chi-square tests were used to analyse the data., Results: Only 31.9% of participants reported visiting a dentist in the past while 36.7% reported experiencing a dental problem at some point in their life. There were no significant differences in utilization of dental services based on gender, socio-economic status, age groups and religion. However, significant differences were found in utilization of dental services based on the response of participants to past experience of dental problems., Conclusion: The present study results conclude that fear was one of the most commonly reported barriers for utilisation of dental services and there is a need for oral health education and promotion among elderly population.

Three series of novel 3,5-bis(arylmethylene)-1-(N-(ortho-substituted aryl)maleamoyl)-4-piperidones, designed as simplified analogs of curcumin with maleic diamide tether, were synthesized and bioevaluated. These compounds displayed potent cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 leukemic cells. In contrast, the related N-arylmaleamic acids possessed little or no cytotoxicity in these three screens. Design of these compounds was based on molecular modeling studies performed on a related series of molecule in a previous study. Representative title compounds were found to be significantly potent in inhibiting the activity of topoisomerase II alpha indicating the possible mode of action of these compounds. These compounds were also potent antioxidants in vitro and attenuated the AAPH triggered peroxyl radical production in human fibroblasts. Various members of these series were also well tolerated in both in vitro and in vivo toxicity analysis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: National oral health policy was conscripted by the Indian Dental Association (IDA) in 1986 and was accepted as an integral part of National Health Policy (NHP) by the Central Council of Health and Family Welfare in one of its conferences in the year 1995. Objectives of this paper were to find out the efforts made or going on towards its execution, its current status and recent oral health-related affairs or programs, if any., Methods: Literature search was done using the institutional library, web-based search engines like 'Google' and 'PubMed' and also by cross referencing. It yielded 108 articles, of which 50 were excluded as they were not pertinent to the topic. Twenty-four were of global perspective rather than Indian and hence were not taken into account and finally 34 articles were considered for analyses. Documents related to central and state governments of India were also considered., Results: All the articles considered for analysis were published within the past 10 years with gradual increase in number which depicts the researchers' increasing focus towards oral health policy. Criticisms, suggestions and recommendations regarding national oral health programs, dental manpower issues, geriatric dentistry, public health dentistry, dental insurance, oral health inequality, and public-private partnerships have taken major occupancies in the articles. Proposals like "model for infant and child oral health promotion" and "oral health policy phase 1 for Karnataka" were among the initiatives towards national oral health policy., Conclusion: The need for implementation of the drafted oral health policy with modification that suits the rapidly changing oral health system of this country is inevitable., (© 2015 by Kerman University of Medical Sciences.)

Context: This invitro study was conducted to compare and evaluate marginal discrepancy in two types of tooth colored self cure provisional restorative materials {DPI&UNIFAST TRAD} before and after reinforcement of glass beads., Aim: The aim of the present study was to evaluate and compare marginal discrepancy in two types of provisional restorative materials (DPI and UNI FAST TRAD) before and after reinforcement with Glass beads., Materials and Methods: Tooth shaped resin copings were fabricated on custom made brass metal die. A total of 60 resin copings were fabricated in which 30 samples were prepared with DPI and 30 samples with UNIFAST material. Each group of 30 samples were divided in to two sub groups in which 15 samples were prepared with glass bead reinforcement and 15 samples without reinforcement. The marginal discrepancy was evaluated with photomicroscope {Reichet Polyvar 2 met} by placing the resin copings on custom made brass resin coping holder., Results: Measurements obtained were statistically analysed by unpaired t-test to know any significance between two variables. Unreinforced DPI specimens had shown lower marginal discrepancy (442.82) than reinforced specimens (585.77). Unreinforced UNIFAST specimens have shown high values of marginal discrepancy (592.83) than reinforced specimens (436.35). p-value between reinforced and unreinforced specimens of DPI (p=0.0013) and UNIFAST (p= 0.0038) has shown statistical significance., Conclusion: This in-vitro study revealed that unreinforced DPI specimens have shown lower marginal discrepancy than reinforced specimens and unreinforced UNIFAST specimens have shown higher values of marginal discrepancy than reinforced specimens.

Background: The oral disease burden in India is showing a steady increase in the recent years. Utilization of dental care being the major factor affecting the oral health status of the population is used as an important tool in oral health policy decision-making and is measured in terms of the number of dental visits per annum., Materials and Methods: A cross-sectional house to house questionnaire survey was conducted in three rural clusters which were randomly selected from a total of eight clusters served by a primary health center. Simple random sampling was used to select 100 houses from each cluster. Screening was done to examine the existing oral diseases. A total of 385 completed questionnaires were collected from 300 houses., Results: Of 385 study subjects, 183 have experienced previous dental problems. Major dental problem experienced by the study subjects was toothache (68.85%) and the treatment underwent was extraction (50.27%). Most preferred treatment centers by the study subjects were private dental hospital (68.25%) and reason identified was accessibility which constituted (45.24%) of all the reasons given. Negative attitude toward dental care is one of the important barriers; 50.8% of the non-utilizers felt dental treatment is not much important., Conclusion: Person's attitude, lack of awareness, and affordability remain the barriers for utilization of dental services. Effective methods have to be exercised to breach such barriers.

Curcumin is widely known for its antioxidant, anti-inflammatory, and antiproliferative activities in cell-culture studies. However, poor oral bioavailability limited its efficacy in animal and clinical studies. Recently, we developed polymeric curcumin implants that circumvent oral bioavailability issues, and tested their potential against 17β-estradiol (E2)-mediated mammary tumorigenesis. Female Augustus Copenhagen Irish (ACI) rats were administered curcumin either via diet (1,000 ppm) or via polymeric curcumin implants (two 2 cm; 200 mg each; 20% drug load) 4 days before grafting a subcutaneous E2 silastic implant (1.2 cm, 9 mg E2). Curcumin implants were changed after 4.5 months to provide higher curcumin dose at the appearance of palpable tumors. The animals were euthanized after 3 weeks, 3 months, and after the tumor incidence reached >80% (~6 months) in control animals. The curcumin administered via implants resulted in significant reduction in both the tumor multiplicity (2 ± 1 vs. 5 ± 3; P = 0.001) and tumor volume (184 ± 198 mm(3) vs. 280 ± 141 mm(3); P = 0.0283); the dietary curcumin, however, was ineffective. Dietary curcumin increased hepatic CYP1A and CYP1B1 activities without any effect on CYP3A4 activity, whereas curcumin implants increased both CYP1A and CYP3A4 activities but decreased CYP1B1 activity in the presence of E2. Because CYP1A and CYP3A4 metabolize most of the E2 to its noncarcinogenic 2-OH metabolite, and CYP1B1 produces potentially carcinogenic 4-OH metabolite, favorable modulation of these CYPs via systemically delivered curcumin could be one of the potential mechanisms. The analysis of plasma and liver by high-performance liquid chromatography showed substantially higher curcumin levels via implants versus the dietary route despite substantially higher dose administered.

Polymeric implants (millirods) have been tested for local delivery of chemotherapeutic agents in cancer treatment. Modeling of drug release profiles is critical as it may provide theoretical insights on rational implant design. In this study, a biodegradable poly (ε-caprolactone) (PCL) polymeric implant delivery system was tested to deliver green tea polyphenols (GTPs), both in vitro and in vivo. Factors including polymer compositions, supplements, drug loads, and surface area of implants were investigated. Our data showed that GTPs were released from PCL implants continuously for long durations, and drug load was the main determining factor of GTPs release. Furthermore, rates of in vitro release and in vivo release in the rat model followed similar kinetics for up to 16 months. A mathematical model was deduced and discussed. GTP implants have the potential to be used systemically and locally at the tumor site as an alternative strategy., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

To evaluate effect of HPV and smoking on DNA double-strand breaks in vaginal samples, vaginal specimens collected from participants (n=76) were classified based on HPV and smoking status, and DNA double-strand breaks measured using comet assay. Mean tail length (31.2±18.7μm) and tail moment (2.4±2.8 arbitrary units) for HPV-positive patients were lower (p<0.001) compared with HPV-negative patients (61.7±22.6μm; 8.7±4.9AU). Never-smokers were found to have a higher level (p<0.001) of double-strand breaks (57.7±24.5μm, 7.5±5.5AU) compared with ever smokers (35.3±21.9μm; 3.4±3.7AU). Among HPV infected patients, never-smokers have more double-strand breaks compared to smokers (p<0.001) which correlated with age (p<0.001). Highly differentiated vaginal epithelium may be resistant to DNA damage associated with HPV infection and smoking, which may be attributed to adoptive survival mechanisms of vaginal epithelium., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We previously demonstrated the protective effects of blueberry (BB) and black raspberry (BRB) supplemented at 2.5% dose in an ACI rat mammary tumor model. Here, we assessed a dose-related alteration in tumor indices with diet supplemented with 5% BB or BRB powder. The diet was well tolerated. Tumor palpation from 12 weeks revealed first tumor appearance by 84 days in the control group, that was delayed by 24 and 39 days with the BB and BRB diets, respectively (p = 0.04). Ellagic acid detected in the plasma of rats fed the BRB diet was in the range of 96.6-294.2 ng/mL. While the BB diet showed better efficacy in reducing mammary tissue proliferation and tumor burden, tumor latency was delayed efficiently by BRB. Furthermore, BB was effective in downregulating CYP1A1 expression, while BRB downregulated ERα expression effectively. Distinct anticarcinogenic effects of the two berries correspond to their distinct phytochemical signatures.

Curcumin possesses potent anti-inflammatory and anti-proliferative activities but with poor biopharmaceutical attributes. To overcome these limitations, curcumin implants were developed and tissue (plasma, brain and liver) curcumin concentrations were measured in female ACI rats for 3 months. Biological efficacy of tissue levels achieved was analyzed by modulation of hepatic cytochromes. Curcumin implants exhibited diffusion-mediated biphasic release pattern with ∼2-fold higher in vivo release as compared to in vitro. Plasma curcumin concentration from implants was ∼3.3 ng/ml on day 1, which dropped to ∼0.2 ng/ml after 3 months, whereas only 0.2-0.3 ng/ml concentration was observed from 4-12 days with diet and was undetected subsequently. Almost 10-fold higher curcumin levels were observed in brain on day 1 from implants compared with diet (30.1 ± 7.3 vs 2.7 ± 0.8 ng/g) and were still significant even after 90 days (7.7 ± 3.8 vs 2.2 ± 0.8 ng/g). Although curcumin levels were similar in liver from both the routes (∼25-30 ng/g from day 1-4 and ∼10-15 ng/g at 90 days), implants were more efficacious in altering hepatic CYP1A1 levels and CYP3A4 activity at ∼28-fold lower doses at 90 days. Curcumin implants provided much higher plasma and tissue concentrations and are a viable alternative for delivery of curcumin to various organs like brain., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Many carcinogenesis and tumorigenesis studies reported in the past several decades have relied upon bolus dose(s) of test compounds to determine their DNA damage and carcinogenic potential. The high doses are far from the human scenario where exposure is almost always to low doses and for long duration. In this study, we report a novel polymeric implant system that provides continuous ("24/7") exposure to low doses using benzo[a]pyrene (BP) as a model carcinogen. Cylindrical implants (1 cm length, 3.2 mm diameter; 10 mg BP/100 mg implant) prepared from polycaprolactone:F68 (9:1) showed controlled release in vitro for long duration. To determine the rate of release and biochemical effects in vivo, groups of female Sprague-Dawley rats received either no treatment or subcutaneous sham or BP implants (1 cm, 10% load) and were euthanized after 6, 15, 30, and 180 days; the average dose of BP by the implant route was 16.7 ± 3 μg/rat. For comparison, rats were also treated with a single bolus dose of BP intraperitoneally (10 mg/rat) and euthanized at 6, 15, and 30 days. DNA adducts analyzed by (32)P-postlabeling in the lung and liver increased steadily with time with levels reaching 31 ± 3 and 17 ± 6 adducts/10(9) nucleotides, respectively, after 25 weeks; the adduct burden in the mammary tissue initially increased but then declined with time presumably due to high cell turn over. In contrast, the bolus dose treatment showed the highest DNA adduct levels after 6 days, followed by a steady decline. The steady accumulation of tissue DNA adducts in the implant groups corroborates the sustained overexpression of CYP1A1 and 1B1, the cytochrome P450s involved in the conversion of BP to its electrophilic metabolites. In contrast, the overexpression of CYP1A1 and 1B1 resulting from the bolus dose of BP lasted only for a few days. This is the first demonstration revealing that low-dose, continuous exposure to environmental polycyclic aromatic hydrocarbons such as BP can render sustained expression of CYPs and steady accumulation of tissue DNA adducts. On the basis of our recent study in which we showed the presence of 17β-estradiol in the lung, the sustained overexpression of CYP1A1 and 1B1 due to continuous exposure to BP may increase the susceptibility to estrogen-mediated carcinogenicity.

Many chemopreventives that show efficacy in vitro show little/no response or require bolus doses in animal models and clinical trials because of limited bioavailability. Ellagic acid has been tested in various animal models with mixed results. We report the efficacy of ellagic acid delivered by a subcutaneous implant compared with a dietary route against estrogen-induced mammary tumors. Ellagic acid delayed the first tumor appearance by 2 and 3 weeks by implant and diet routes, respectively. The tumor incidence was 75% and 69% by the implant and dietary routes when the control group had 100% palpable tumors by 26 weeks. Ellagic acid also significantly reduced the tumor burden by both implant (855±242 mm; P=0.0375) and dietary (599±169 mm; P=0.0133) routes compared with control (1522±299 mm). Similar reductions were observed in tumor multiplicity (4.8±0.5; P=0.0042 and 4.5±0.4; P=0.0031 tumors/rat with implant and diet, respectively, vs. 8.9±1.2 in control). The total amount of ellagic acid administered by implant was 5.92±3.48 whereas it was 800±40 mg/rat through diet. Thus, over 130-fold dose reduction produced similar biological responses when delivered by implant. The anticarcinogenicity effects corroborated the observed reduction in levels of pituitary prolactin. This novel approach opens new avenues to test agents individually or as mixtures for their chemopreventive potential that are discontinued, either due to lack of bioavailability or toxicity potentially associated with high doses or due to lack of availability of sufficient quantities.

Exposure to cigarette smoke is well documented to increase oxidative stress and could account for higher risk of cervical cancer in smokers. Cervical pre-cancerous lesions that are initiated by human papillomavirus (HPV) infection generally regress in the absence of known risk factors such as smoking. 8-oxodeoxyguanosine (8-oxodG) is a highly mutagenic oxidative DNA lesion that is formed by the oxidation of deoxyguanosine. In the present study, we examined: a) the effect of cigarette smoke condensate (CSC) on 8-oxodG formation in and its removal from HPV-transfected (ECT1/E6 E7), HPV-positive (CaSki) and HPV-negative (C33A) human cervical cancer cells, and b) the cell cycle progression and apoptosis in CSC-treated ECT1/E6 E7 cells. CSC induced 8-oxodG in a dose- (p=0.03) and time (p=0.002)-dependent fashion in ECT1/E6 E7 cells as determined by flow cytometry. A 2.4-fold higher level of 8-oxodG was observed in HPV-positive compared with HPV-negative cells. However, 8-oxodG lesions were almost completely removed 72 h post-exposure in all cell lines as determined by ImageStream analysis. This observation correlates with the 2- and 5-fold increase in the p53 levels in ECT1/E6 E7 and CaSki cells with no significant change in C33A cells. We conclude that: a) cigarette smoke constituents induce oxidative stress with higher burden in HPV-positive cervical cancer cells and b) the significant increase observed in p53 levels in wild-type cervical cells (ECT1/E6 E7 and CaSki) may be attributed to the p53-dependent DNA repair pathway while a p53-independent pathway in C33A cells cannot be ruled out.

Curcumin, an anti-oxidant, anti-inflammatory, and anti-neoplastic agent, exhibited limited oral efficacy due to its poor bioavailability. To overcome this limitation, polymeric implants for continuous systemic delivery of curcumin were developed and tested for their safety and biocompatibility. Two 2-cm polycaprolactone implants containing polyethylene glycol and 20% (w/w) curcumin were grafted subcutaneously at the back of the Augustus Copenhagen Irish rats. Rats were euthanized and blood was analyzed for various hematological parameters; biochemical markers of liver/kidney function and local tissues were analyzed for local inflammatory reactions. Curcumin implants exhibited biphasic release kinetics with ∼3.6 + 0.8, 5.8 ± 1.1, 13.1 ± 2.1, 21.8 ± 0.3, 38.1 ± 0.6, and 47.2 ± 1.6 mg cumulative curcumin being released from both the implants after 1, 4, 12, 25, and 90 days. No significant differences in various hematological parameters (like white blood cells, red blood cells, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin), liver enzymes (like aspartate transaminase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, amylase, or lipase), or biochemical parameters of kidney function (like blood urea nitrogen, creatinine, Ca(2+), Na(+), and Cl(-) levels) were observed at any of these time points. However, a significant increase in serum phosphorus levels was observed at all the time points in sham implants as well as in curcumin diet and implant groups. Local implantation site showed foreign body granulomatous reaction with influx of histiocytes and occasional multi-nucleated giant cells with sham implants and was minimal around the curcumin implants. These polymeric implants were found to have little or no systemic toxicity with an acute reaction at local site which was reduced significantly by curcumin implants.

Dietary habits that expose populations to potential toxicants as well as protective agents simultaneously are a realistic scenario where a meaningful assessment of the interactions and net benefit or damage can be made. A group of Inuit from Salluit, Northern Canada are exposed to high levels of PCBs and selenium, both present in the Inuit traditional foods such as blubber from sea mammals and fatty fish. Blood samples were collected from 83 Inuit, 22-70 years old. Blood selenium and PCB levels were determined previously and ranged from 227 to 2069µg/L and 1.7 to 143µg/L, respectively. DNA isolated from white blood cells were analyzed by modified (32)P-postlabeling adductomics technology that detects a multitude of highly polar to lipophilic adducts. The levels of 8-oxodG adducts ranged from 470 to 7400 adducts/10(9) nucleotides. Other as yet unidentified polar adducts showed a 30 to 800-fold inter-individual variability. Adduct levels were negatively associated with PCB and selenium levels. The subjects were classified into high and low ratio groups, with respect to selenium/PCB. In the high ratio group, the coefficient of selenium is significantly negatively correlated with 8-oxodG (r = -0.38, p = 0.014) and total adducts (r = -0.41, p = 0.009) while there was no correlation within the low selenium/PCB group. This study suggests that increasing selenium has mitigating effect in reducing DNA adducts and therefore, possible negative effects of PCB were not seen. A protective effect of selenium is highlighted., (Copyright © 2009 Elsevier Ltd. All rights reserved.)

Human papillomavirus (HPV) is the causative factor in the development and progression of cervical cancers in >97% of the cases, although insufficient. Epidemiological studies suggest an elevated risk of cervical cancer for cigarette smokers; therefore, we examined cigarette smoke-induced DNA damage and repair in HPV16-transformed human ectocervical cells (ECT1/E6 E7). Cells were treated with cigarette smoke condensate (CSC) for 72 h to assess the formation of single- and double-strand DNA breaks, measured by alkaline and neutral single cell gel electrophoresis assays, respectively. The mean tail length of cells with single-strand breaks was increased by 1.8-, 2.7- and 3.7-fold (p<0.001) after treatment with 4, 8 and 12 microg/ml CSC, respectively. The tail length with double-strand breaks was also increased dose-dependently. These results were further supported by measurement of the mean tail moment: the increase in both single- and double-strand breaks were much more pronounced with increasing concentration of CSC, by up to 23.5-fold (p<0.0001 for both assays). To examine the DNA repair, cells were treated with CSC for 72 h, followed by CSC withdrawal and re-incubation of the cells with fresh medium for 24, 48, or 72 h. Both single- and double-strand DNA breaks were removed during the initial 24 h but no further removal of the damage was observed. Up to 80% of residual single- and double-strand DNA breaks (p<0.05) were found to persist at all CSC concentrations examined. Ellagic acid, a known antioxidant and free-radical scavenger, was found to significantly inhibit DNA breaks induced by CSC. Thus, free radicals may be a plausible source of CSC-induced DNA damage. These data show that CSC-mediated DNA strand breaks are highly persistent, and suggest that persistence of cigarette smoke-associated DNA damage in the presence of HPV infection may lead to increased mutations in cervical cells and ultimately higher cancer risk.

Lower chlorinated PCBs can damage DNA directly or via free radical mechanisms. In order to assess the DNA-damaging potential of PCBs in humans, blood samples were collected from Inuit population from Salluit, Northern Canada. Their diet comprises blubber from sea mammals and fatty fish, which accumulate non-biodegradable PCBs at varying levels. The 103 samples thus collected were categorized into low-, medium- and high-PCB exposure groups. A comprehensive (32)P-postlabeling adductomics technology, which allows measure differences in DNA adduct profiles of polar and lipophilic adducts between control and exposure groups, was applied to these samples to assess the effect of PCB on DNA damage. The adduct patterns obtained were qualitatively similar to other human tissues studied previously. A range of highly polar to lipophilic subgroups of adducts were detected. The known oxidative lesion, 8-oxodG was predominant. While some individual adducts appear to accumulate with increasing PCB levels, a definitive association could not be made. A possible confounder effect of selenium is discussed., (Copyright © 2007 Elsevier B.V. All rights reserved.)

Colon cancer is second leading cause of cancer-related deaths in Western countries. Diet and smoking, which contain aromatic and heterocyclic amines, are major risk factors for colon cancer. Colorectal cancers have a natural history of long latency and therefore provide ample opportunities for effective chemoprevention. 3,2'-Dimethyl-4-aminobiphenyl (DMABP) is an experimental aromatic amine that causes cancer in rat colon and serves as an experimental model for arylamine and heterocyclic amine mutagens derived from diet and smoking. In this study, we investigated the effects of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor on DMABP-induced DNA adduct formation in rat liver and colon. Male F-344 rats (5-week old) were provided free access to modified AIN-76A rat chow containing 0 (control), 500, 1000, or 1500 ppm celecoxib. Two weeks later, the rats received a subcutaneous injection of 100mg/kg DMABP in peanut oil. Two days after DMABP treatment, the rats were killed and DMABP-derived adducts were analyzed in colon and liver DNA by butanol extraction-mediated (32)P-postlabeling. Two major DNA adducts, identified as dG-C8-DMABP and dG-N(2)-DMABP, were detected in liver and colon of rats treated with DMABP. These DNA adducts were diminished approximately 35-40% with 500 ppm and 65-70% with 1,000 ppm celecoxib. In the colon, no further decline in DNA adducts was observed at 1500 ppm. The same DMABP-DNA adducts also were detected in the liver and were also diminished by celecoxib treatment. The reduction in DMABP-DNA adduct levels in celecoxib-treated animals provides further support for celecoxib as a chemopreventive agent for colorectal cancer.

Animal models play a major role in understanding the etiology, molecular mechanisms, strategizing intervention and treatment of human diseases. ACI, an inbred line derived from August and Copenhagen strains, is unique for its susceptibility to estrogen-induced mammary tumors. Histologically and in many molecular aspects, the tumors formed in these rats are similar to human breast cancers. Previous studies have shown high mortality and significant weight loss in this model associated with pituitary gland abnormality. We hypothesized that this could be due to overwhelming the biological system with estrogen. Three groups of female ACI rats (7-8 weeks) received either 3-cm sham silastic implants, or the conventional 3-cm silastic implants containing 27 mg of 17beta-estradiol, or 1.2-cm silastic implants containing 9 mg 17beta-estradiol. The sham and 3-cm implant rats were euthanized at 180 days while the 1.2-cm implant rats were euthanized at 240 days. The 1.2-cm implants resulted in significantly reduced serum estrogen levels and pituitary gland size. Animals with 1.2-cm implants had 100% tumor incidence, while not all rats developed tumors with 3-cm implants. Both the tumor burden (from 1,011+/-402 to 2,324+/-454 mm(3); p=0.01) and tumor multiplicity (from 5.78+/-1.4 to 7.6+/-1.04) increased by lowering the estrogen dose, and the inter-animal variability in the tumor indices decreased. Finally, the weight of the pituitary gland was also significantly (p=0.0004) reduced (from 178+/-23.5 mg to 80+/-8.9 mg) and the mortality rate decreased from 42% to 0% (p=0.01). Our data indicate that the improvised model will provide valuable insights into the molecular alterations in the estrogen-induced mammary tumorigenesis and will be ideal for inhibition studies.

Progressive accumulation of DNA lesions leads to genetic mutations that are central to the process of tumorigenesis. Human cervix provides an ideal system to determine progressive accumulation of DNA adducts in the target tissue because of its accessibility during routine diagnostic checkups. Uterine cervix samples from various pathologies, i.e. normal (n=13), inflammation (n=9), dysplasia (n=5) and different stages of invasive cancer (n=47), were analyzed for DNA adduct burden by modified 32P-postlabeling/TLC systems. Six subgroups of adducts were detected in the following descending order of polarities: P-1, P-2, PL-1, PL-2, L-1 and L-2 (P, polar; L, lipophilic; PL, between polar and lipophilic). No qualitative differences were observed in adduct profiles in the various cervix pathologies analyzed. However, significant quantitative differences were found. Previously known lipophilic adducts increased significantly from normal to cancer (144+/-61 to 503+/-51 adducts/10(9) nucleotides). Interestingly, the newly discovered polar adducts were present at 61- to 527-fold higher levels than lipophilic adducts. Of all the polar adducts, the known mutagenic lesion, 8-oxodeoxyguanosine, predominated in all cervix conditions. Notably, this lesion was elevated 27-fold in inflammation compared with normal cervix (51,058+/-9,863 versus 1,886+/-507 adducts/10(9) nucleotides). The P-1, PL-1, PL-2 and L-1 adducts were elevated 3- to 13-fold in inflammation compared with normal cervix, and were also higher in dysplasia and cancer. Our data suggest that inflammation may be involved in directing the course of disease progression by accumulating higher levels of DNA lesions. The data further suggest the biomarker potential of the newly detected array of DNA adducts.