Significance of Increased Tissue Transglutaminase in Hormone Refractory Prostate Cancer

The progression of hormone responsive to hormone refractory prostate cancer poses a major clinical challenge in the successful treatment of prostate cancer. The hormone refractory prostate cancer cells exhibit resistance not only to castrate levels of testosterone, but also to other therapeutic modalities and hence become lethal. Currently, there is no effective treatment available for managing this cancer. These observations underscore the urgency to investigate mechanism(s) that contribute to the progression of hormone-responsive to hormone-refractory prostate cancer and to target them for improved clinical outcomes. Tissue transglutaminase (TG2) is a multifunctional pro-inflammatory protein involved in diverse physiological processes such as inflammation, tissue repair, and wound healing. Its expression is also implicated in pathological conditions such as cancer and fibrosis. Interestingly, we found that the androgen-independent prostate cancer cell lines, which lacked androgen receptor (AR) expression, contained high basal levels of tissue transglutaminase. Inversely, the cell lines that expressed androgen receptor lacked transglutaminase expression. This attracted our attention to investigate the possible role this protein may play in the progression of prostate cancer, especially in view of recent observations that its expression is linked with increased invasion, metastasis, and drug resistance in multiple cancer cell types. The results we obtained were rather surprising and revealed that stable expression of tissue transglutaminase in androgen-sensitive LNCaP prostate cancer cells rendered these cells independent of androgen for growth and survival by silencing the AR expression. The AR silencing in TG2 expressing cells (TG2-infected LNCaP and PC-3 cells) was due to TG2-induced activation of the inflammatory nuclear transcription factor-kB (NF-kB). Thus, TG2 induced NF-kB was found to directly bind to the AR promoter. Importantly, TG2 protein was specifically recruited to the AR promoter in complex with the p65 subunit of NF-kB. Moreover, TG2 expressing LNCaP and PC-3 cells exhibited epithelial-to-mesenchymal transition, as evidenced by gain of mesenchymal (such as fibronectin, vimentin, etc.) and loss of epithelial markers (such as E-cadherin, b-catenin). Taken together, these results suggested a new function for TG2 and revealed a novel mechanism that is responsible for the progression of prostate cancer to the aggressive hormone-refractory phenotype.

Food Insecurity and Children: Hunger?… In America?... How is that possible?

Despite being one of the wealthiest nations in the world, the United States continues to be plagued by the problem of food insecurity, especially at the child level. The editors' implications piece presents a call for greater urgency in addressing the problem of food insecurity in the United States.

Mechanisms of Ad-p53 induced apoptosis in human malignant glioma

Malignant brain tumors are one of the most challenging cancers affecting society today. In a recent survey, an estimated 17,000 annual cases were recorded with a staggering total of 13,300 deaths. A unique degree of heterogeneity typifies glial tumors and presents a challenge for solitary anti-neoplastic treatments. Tumors subsist as heterogeneous masses that progress through dysplasia to astrocytomas, mixed glioma and glioblastoma multiforme. Although traditional therapeutic approaches have provided increments of success, the median survival time remains 12 months. The urgency to improve upon current clinical protocols has encouraged alternative experimental strategies such as p53 adenoviral gene therapy (Ad-p53). This study addresses the efficacy of Ad-p53 for the treatment of glioma. Our model presents a tumor response that is unique among human cancers. Ad-p53 effectively induces apoptosis in mutant p53 expressing cells yet fails to do so in those with wildtype p53. In order to adopt Adp53 as a standard anti-cancer modality, we characterized the role of the tumor suppressor gene p53 in mediating apoptosis. We demonstrate that altering cellular p53 status through the introduction of a dominant negative mutant p53 (175H, 248W, 273H) sensitized cells to Ad-p53. We discovered that wild-type p53 expressing glioma cells retain the apoptotic machinery necessary to accomplish cell death, but have developed mechanisms that interfere with p53 signaling. Earlier studies have not addressed the mechanisms of Ad-p53 apoptosis nor the resistance exhibited by wild-type p53 glioma. To explain the divergent phenotypes, we identified apoptotic pathways activated and effectors of the response. We illustrated that modulation of the death receptor Fas/APO-1 is a principal means of Ad-p53 signaling that is impaired in wild-type p53 glioma. Moreover, the apoptotic response was found to be a multi-faceted process that engaged several caspases, most notably caspases -1, -3 and -8. Lastly, we assessed the ability of anti-apoptotic molecules Bcl-2 and CrmA to inhibit Ad-p53 apoptosis. These studies revealed that Ad-p53 is a powerful tool for inducing apoptosis that can be delayed but not inhibited by anti-apoptotic means. This work is critical for understanding the development of glioma and the phenotypic and genotypic alterations that account for tumor resistance. ^

Analysis of Mycobacterium tuberculosis in the state of Texas for rifampin resistance using molecular beacons

Mycobacterium tuberculosis, a bacillus known to cause disease in humans since ancient times, is the etiological agent of tuberculosis (TB). The infection is primarily pulmonary, although other organs may also be affected. The prevalence of pulmonary TB disease in the US is highest along the US-Mexico border, and of the four US states bordering Mexico, Texas had the second highest percentage of cases of TB disease among Mexico-born individuals in 1999 (CDC, 2001). Between the years of 1993 and 1998, the prevalence of drug-resistant (DR) TB was 9.1% among Mexican-born individuals and 4.4% among US-born individuals (CDC, 2001). In the same time period, the prevalence of multi-drug resistant (MDR) TB was 1.4% among Mexican-born individuals and 0.6% among US-born individuals (CDC, 2001). There is a renewed urgency in the quest for faster and more effective screening, diagnosis, and treatment methods for TB due to the resurgence of tuberculosis in the US during the mid-1980s and early 1990s (CDC, 2007a), and the emergence of drug-resistant, multidrug-resistant, and extremely drug-resistant tuberculosis worldwide. Failure to identify DR and MDR-TB quickly leads to poorer treatment outcomes (CDC, 2007b). The recent rise in TB/HIV comorbidity further complicates TB control efforts. The gold standard for identification of DR-TB requires mycobacterial growth in culture, a technique taking up to three weeks, during which time DR/MDR-TB individuals harboring resistant organisms may be receiving inappropriate treatment. The goal of this study was to determine the sensitivity and specificity of real-time quantitative polymerase chain reaction (qPCR) using molecular beacons in the Texas population. qPCR using molecular beacons is a novel approach to detect mycobacterial mutations conferring drug resistance. This technique is time-efficient and has been shown to have high sensitivity and specificity in several populations worldwide. Rifampin (RIF) susceptibility was chosen as the test parameter because strains of M. tuberculosis which are resistant to RIF are likely to also be MDR. Due to its status as a point of entry for many immigrants into the US, control efforts against TB and drug-resistant TB in Texas is a vital component of prevention efforts in the US as a whole. We show that qPCR using molecular beacons has high sensitivity and specificity when compared with culture (94% and 87%, respectively) and DNA sequencing (90% and 96%, respectively). We also used receiver operator curve analysis to calculate cutoff values for the objective determination of results obtained by qPCR using molecular beacons. ^

Air Force Web Preventive Health Assessment (AF WEBPHA) mental health screening effectiveness

The U.S. Air Force assesses Active Duty Air Force (ADAF) health annually using the Air Force Web-based Preventative Health Assessment (AF WebPHA). The assessment is based on a self-administered survey used to determine the overall Air Force health and readiness, as well as, the individual health of each airman. Individual survey responses as well as groups of responses generate further computer generated assessment and result in a classification of 'Critical', 'Priority', or 'Routine', depending on the need and urgency for further evaluation by a health care provider. The importance of the 'Priority' and 'Critical' classifications is to provide timely intervention to prevent or limit unfavorable outcomes that may threaten an airman. Though the USAF has been transitioning from a paper form to the online WebPHA survey for the last three years it was not made mandatory for all airmen until 2009. The survey covers many health aspects including family history, tobacco use, exercise, alcohol use, and mental health. ^ Military stressors such as deployment, change of station, and the trauma of war can aggravate and intensify the common baseline worries experienced by the general population and place airmen at additional risks for mental health concerns and illness. This study assesses the effectiveness of the AF WebPHA mental health screening questions in predicting a mental health disorder diagnosis according to International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes generated by physicians or their surrogates. In order to assess the sensitivity, specificity, and positive predictive value of the AF WebPHA as a screening tool for mental health, survey results were compared to ascertain if they generated any mental health disorder related diagnosis for the period from January 1, 2009 to March 31, 2010. ^ Statistical analysis of the AF WebPHA mental health responses when compared with matching ICD-9-CM codes found that the sensitivity for 'Critical' or 'Priority' responses was only 3.4% and that it would correctly predict those who had the selected mental health diagnosis 9% of the time.^

Assessing and applying evidence-based interventions at the community level in India as a model policy to reduce neonatal mortality rates in Nigeria

Background. The United Nations' Millennium Development Goal (MDG) 4 aims for a two-thirds reduction in death rates for children under the age of five by 2015. The greatest risk of death is in the first week of life, yet most of these deaths can be prevented by such simple interventions as improved hygiene, exclusive breastfeeding, and thermal care. The percentage of deaths in Nigeria that occur in the first month of life make up 28% of all deaths under five years, a statistic that has remained unchanged despite various child health policies. This paper will address the challenges of reducing the neonatal mortality rate in Nigeria by examining the literature regarding efficacy of home-based, newborn care interventions and policies that have been implemented successfully in India. ^ Methods. I compared similarities and differences between India and Nigeria using qualitative descriptions and available quantitative data of various health indicators. The analysis included identifying policy-related factors and community approaches contributing to India's newborn survival rates. Databases and reference lists of articles were searched for randomized controlled trials of community health worker interventions shown to reduce neonatal mortality rates. ^ Results. While it appears that Nigeria spends more money than India on health per capita ($136 vs. $132, respectively) and as percent GDP (5.8% vs. 4.2%, respectively), it still lags behind India in its neonatal, infant, and under five mortality rates (40 vs. 32 deaths/1000 live births, 88 vs. 48 deaths/1000 live births, 143 vs. 63 deaths/1000 live births, respectively). Both countries have comparably low numbers of healthcare providers. Unlike their counterparts in Nigeria, Indian community health workers receive training on how to deliver postnatal care in the home setting and are monetarily compensated. Gender-related power differences still play a role in the societal structure of both countries. A search of randomized controlled trials of home-based newborn care strategies yielded three relevant articles. Community health workers trained to educate mothers and provide a preventive package of interventions involving clean cord care, thermal care, breastfeeding promotion, and danger sign recognition during multiple postnatal visits in rural India, Bangladesh, and Pakistan reduced neonatal mortality rates by 54%, 34%, and 15–20%, respectively. ^ Conclusion. Access to advanced technology is not necessary to reduce neonatal mortality rates in resource-limited countries. To address the urgency of neonatal mortality, countries with weak health systems need to start at the community level and invest in cost-effective, evidence-based newborn care interventions that utilize available human resources. While more randomized controlled studies are urgently needed, the current available evidence of models of postnatal care provision demonstrates that home-based care and health education provided by community health workers can reduce neonatal mortality rates in the immediate future.^

Use of universal precautions in the workplace: A comparison of two fire /EMS services

The Health Belief Model (HBM) provided the theoretical framework for examining Universal Precautions (UP) compliance factors by Firefighter, EMTs and Paramedics (prehospital care providers). A convenient sample of prehospital care providers (n = 4000) from two cities (Houston and Washington DC), were surveyed to explore the factors related to their decision to comply with Universal Precautions. Eight hundred and sixty-five useable questionnaires were analyzed. The responders were primarily male (95.7%) eight hundred and twenty-eight and thirty-seven were female, prehospital based (100%), EMTs (60.0%) and paramedics (12.8%) who had a mean 13 years of prehospital care experience. ^ Linear regression was used to evaluate the four hypotheses. The first hypothesis evaluating perceived susceptibility and seriousness with reported UP use was statistically significant (p = < .05). Perceived susceptibility, when considered independently, did not make a significant contribution (t = −4.2852; p = 0.0000) to the stated use of Universal precautions. The hypothesis is not supported as stated. The data indicates the opposite effect. Supported is the premise that as perceived susceptibility and perceived seriousness increase the use of Universal Precautions decreases. Hypothesis two tested perceived benefits with internal and external barriers. Both perceived benefits and internal and external barriers as well as the overall regression were significant (F = 112.6, p = 0.0000). The contribution of internal and external barriers was statistically significant (t = 0.0175; p = 0.0000) and (t = 0.0128; p = 0.0000). Hypothesis three which tested modifying factors, cues to action, select demographic variables, and the main effects of the HBM with self reported UP compliance overall was significant. The variables gender, birth, education, job type, EMS certification, years of service, years of experience providing patient care, Universal Precautions training hours, type of apparatus assigned to and the number of EMS related incidents responded to in a month were found to have a significant contribution to the stated use of Universal Precautions. ^ The additive effects were tested by use of a stepwise regression that assessed the contribution of each of the significant variables. Three variables in the equation were statistically significant. Internal barriers (t = −8.5507; p = 0.0000), external barriers (t = −6.2862; p = 0.000) and job type 2 & 3. Job type two (t = −2.8464; p = 0.0045 is titled Engineer/Operator. Job type three (t = −2.5730; p = 0.0103) is titled captain. The overall regression was significant (F = 24.06; p = 0.000). The Hypothesis is supported in the certain demographic variables do influence the stated use of Universal precautions and that as internal and external barriers are decreased, there is an increase in the stated use of Universal Precautions. ^ In summary, this study demonstrated that internal and external barriers have a significant impact on the stated use of Universal Precautions. Internal barriers are those factors within the individual that require an internal change (i.e., forgetfulness, freedom, perception of the urgency of the patient's needs etc.) and external barriers are things in the environment that can be altered (i.e., equipment design, availability of equipment, ease of use). These two model variables explained 23%–30% of the variance. ^