Research enrichment: evaluation of structured research in the curriculum for dental medicine students as part of the vertical and horizontal integration of biomedical training and discovery

<p>Abstract</p> <p>Background</p> <p>Research programs within medical and dental schools are important vehicles for biomedical and clinical discovery, serving as effective teaching and learning tools by providing situations in which predoctoral students develop problem-solving and critical-thinking skills. Although research programs at many medical and dental schools are well-established, they may not be well integrated into the predoctoral curriculum to effectively support the learning objectives for their students.</p> <p>Methods</p> <p>A series of structured seminars, incorporating faculty research, was designed for first-year dental students at the University of Nevada, Las Vegas, School of Dental Medicine to reinforce and support the concepts and skills taught in concurrent courses. A structured research enrichment period was also created to facilitate student engagement in active research using faculty and student curricular release time. Course evaluations and surveys were administered to gauge student perceptions of the curricular integration of research, the impact of these seminars on recruitment to the research program, and overall levels of student satisfaction with research enrichment.</p> <p>Results</p> <p>The analysis of course surveys revealed that students perceived the research-containing seminars effectively illustrated concepts, were logically sequenced, and were well-integrated into their curriculum. In addition, analysis of surveys revealed that the Integration Seminar courses motivated students to engage in research enrichment. Finally, this analysis provided evidence that students were very satisfied with their overall learning experience during research enrichment.</p> <p>Conclusion</p> <p>Curricular integration is one method of improving the teaching and learning of complicated and inter-related concepts, providing an opportunity to incorporate research training and objectives into traditionally separate didactic courses. Despite the benefits of curricular integration, finding the most appropriate points of integration, obtaining release time for curricular development and for research engagement, and funding predoctoral student research remain issues to be addressed in ways that reflect the character of the faculty and the goals of each institution.</p

High-risk human papillomavirus (HPV) screening and detection in healthy patient saliva samples: a pilot study

<p>Abstract</p> <p>Background</p> <p>The human papillomaviruses (HPV) are a large family of non-enveloped DNA viruses, mainly associated with cervical cancers. Recent epidemiologic evidence has suggested that HPV may be an independent risk factor for oropharyngeal cancers. Evidence now suggests HPV may modulate the malignancy process in some tobacco- and alcohol-induced oropharynx tumors, but might also be the primary oncogenic factor for inducing carcinogenesis among some non-smokers. More evidence, however, is needed regarding oral HPV prevalence among healthy adults to estimate risk. The goal of this study was to perform an HPV screening of normal healthy adults to assess oral HPV prevalence.</p> <p>Methods</p> <p>Healthy adult patients at a US dental school were selected to participate in this pilot study. DNA was isolated from saliva samples and screened for high-risk HPV strains HPV16 and HPV18 and further processed using qPCR for quantification and to confirm analytical sensitivity and specificity.</p> <p>Results</p> <p>Chi-square analysis revealed the patient sample was representative of the general clinic population with respect to gender, race and age (<it>p </it>< 0.05). Four patient samples were found to harbor HPV16 DNA, representing 2.6% of the total (n = 151). Three of the four HPV16-positive samples were from patients under 65 years of age and all four were female and Hispanic (non-White). No samples tested positive for HPV18.</p> <p>Conclusions</p> <p>The successful recruitment and screening of healthy adult patients revealed HPV16, but not HPV18, was present in a small subset. These results provide new information about oral HPV status, which may help to contextualize results from other studies that demonstrate oral cancer rates have risen in the US among both females and minorities and in some geographic areas that are not solely explained by rates of tobacco and alcohol use. The results of this study may be of significant value to further our understanding of oral health and disease risk, as well as to help design future studies exploring the role of other factors that influence oral HPV exposure, as well as the short- and long-term consequences of oral HPV infection.</p

Expression of transforming growth factor beta-1 in gastric cancer and in the gastric mucosa of first-degree relatives of patients with gastric cancer

Transforming growth factors beta (TGF-β) constitute a family of polypeptide growth factors that control cell growth, cell differentiation and migration, as well as the formation of the extracellular matrix. Recent analyses revealed the overexpression of TGF-β1 in human gastric cancers and demonstrated increased cell proliferation in the stomach of patients with gastric cancer and their first-degree relatives. Using human gastric tissues obtained from patients with gastric cancer (n = 19), biopsies from healthy first-degree relatives of gastric cancer patients (n = 18) and healthy individuals (n = 19), we analysed the expression of TGF-β1 using the reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Fifteen of 19 patients with gastric cancer expressed TGF-β1 in the tumour. In 11 of these 15 cases TGF-β1 mRNA was also detectable in the non-tumourous stomach. Interestingly, all but two individuals with a first-degree relative diagnosed with gastric cancer exhibited TGF-β1 expression in either the antrum or corpus biopsy or both. In contrast, only one of 19 individuals without a family history of gastric cancer expressed TGF-β1 in the stomach (P< 0.0001). TGF-β1 expression is detectable in a large proportion of gastric cancers and in the stomach of healthy first-degree relatives of gastric cancer patients. Since individuals without gastric cancers in their family express TGF-β1 only in one of 19 cases, the induction of TGF-β1 expression in first-degree relatives of patients with gastric cancer points to the presence of specific molecular alterations in a subgroup of individuals with an increased risk of developing gastric cancer that may precede the development of gastric cancers. © 2000 Cancer Research Campaig

Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a

Background Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge. Methods and Findings We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model. Conclusions Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Examining the Incidence of Human Papillomavirus-Associated Head and Neck Cancers by Race and Ethnicity in the U.S., 1995–2005

Background: Head and neck cancer (HNC) incidence, mortality and survival rates vary by sex and race, with men and African Americans disproportionately affected. Risk factors for HNC include tobacco and alcohol exposure, with a recent implication of human papillomavirus (HPV) in the pathogenesis of HNC. This study describes the epidemiology of HNC in the United States, examining variation of rates by age, sex, race/ethnicity and potential HPV-association. Methods: We used the North American Association of Central Cancer Registries (NAACCR) Cancer in North America (CINA) Deluxe Analytic Data to analyze HNC incidence for 1995–2005 from forty population-based cancer registries. We calculated age-adjusted incidence rates and incidence trends using annual percent change by age, sex, race/ethnicity and HPVassociation. Results: Males and Non-Hispanic Blacks experienced greater HNC incidence compared to women and other race/ethnicity groupings. A significant overall increase in HNC incidence was observed among HPV-associated sites during 1995–2005, while non HPV-associated sites experienced a significant decline in HNC incidence. Overall, younger age groups, Non-Hispanic Whites and Hispanics experienced greater increases in incidence for HPV-associated sites, while HNC incidence declined for Non-Hispanic Blacks independent of HPV-association. In particular, for HPV-associated sites, HNC incidence for Non-Hispanic White males aged 45–54 increased at the greatest rate, with an APC of 6.28 % (p,0.05). Among non HPVassociated sites, Non-Hispanic Black males aged 0–44 years experienced the greatest reduction in incidence (APC, 28.17%

Current perspectives on bone metastases in castrate-resistant prostate cancer

Prostate cancer is the most frequent noncutaneous cancer occurring in men. On average, men with localized prostate cancer have a high 10-year survival rate, and many can be cured. However, men with metastatic castrate-resistant prostate cancer have incurable disease with poor survival despite intensive therapy. This unmet need has led to recent advances in therapy aimed at treating bone metastases resulting from prostate cancer. The bone microenvironment lends itself to metastases in castrate-resistant prostate cancer, as a result of complex interactions between the microenvironment and tumor cells. The development of 223radium dichloride (Ra-223) to treat symptomatic bone metastases has improved survival in men with metastatic castrate-resistant prostate cancer. Moreover, Ra-223 may have effects on the tumor microenvironment that enhance its activity. Ra-223 treatment has been shown to prolong survival, and its effects on the immune system are under investigation. Because prostate cancer affects a sizable portion of the adult male population, understanding how it metastasizes to bone is an important step in advancing therapy. Clinical trials that are underway should yield new information on whether Ra-223 synergizes effectively with immunotherapy agents and whether Ra-223 has enhancing effects on the immune system in patients with prostate cancer

Circulating mediators of inflammation and immune activation in AIDS-related non-Hodgkin lymphoma

Background: Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation. Methods: This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed beadbased immunoassays. Results: A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers. Conclusions: These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease. © 2014 Nolen et al

Latent transforming growth factor binding protein 4 (LTBP4) is downregulated in mouse and human DCIS and mammary carcinomas

Transforming growth factor beta (TGF-) is able to inhibit the proliferation of epithelial cells and is involved in the carcinogenesis of mammary tumors. Three latent transforming growth factor- binding proteins (LTBPs) are known to modulate TGF- functions. The current study analyses the expression profiles of LTBP4, its isoforms LTBP1 and LTBP3, and TGF-1, TGF-2, TGF-3, and SMAD2, SMAD3 and SMAD4 in human and murine (WAP-TNP8) DCIS compared to invasive mammary tumors. Additionally mammary malignant (MCF7, Hs578T, MDA-MB361) and non malignant cell lines (Hs578BsT) were analysed. Microarray, q-PCR, immunoblot, immunohistochemistry and immunofluorescence were used. In comparison to non-malignant tissues (n = 5), LTBP4 was downregulated in all human and mouse DCIS (n = 9) and invasive mammary adenocarcinomas (n = 5) that were investigated. We also found decreased expression of bone morphogenic protein 4 (BMP4) and increased expression of its inhibitor gremlin (GREM1). Treatment of the mammary tumor cell line (Hs578T) with recombinant TGF-1 rescued BMP4 and GREM1 expression. We conclude that the lack of LTBP4-mediated targeting in malignant mammary tumor tissues may lead to a possible modification of TGF-1 and BMP bioavailability and function

Genome sequencing reveals diversification of virulence factor content and possible host adaptation in distinct subpopulations of Salmonella enterica

<p>Abstract</p> <p>Background</p> <p>Divergence of bacterial populations into distinct subpopulations is often the result of ecological isolation. While some studies have suggested the existence of <it>Salmonella enterica </it>subsp. <it>enterica </it>subclades, evidence for these subdivisions has been ambiguous. Here we used a comparative genomics approach to define the population structure of <it>Salmonella enterica </it>subsp. <it>enterica</it>, and identify clade-specific genes that may be the result of ecological specialization.</p> <p>Results</p> <p>Multi-locus sequence analysis (MLSA) and single nucleotide polymorphisms (SNPs) data for 16 newly sequenced and 30 publicly available genomes showed an unambiguous subdivision of <it>S. enterica </it>subsp. <it>enterica </it>into at least two subpopulations, which we refer to as clade A and clade B. Clade B strains contain several clade-specific genes or operons, including a β-glucuronidase operon, a S-fimbrial operon, and cell surface related genes, which strongly suggests niche specialization of this subpopulation. An additional set of 123 isolates was assigned to clades A and B by using qPCR assays targeting subpopulation-specific SNPs and genes of interest. Among 98 serovars examined, approximately 20% belonged to clade B. All clade B isolates contained two pathogenicity related genomic islands, SPI-18 and a cytolethal distending toxin islet; a combination of these two islands was previously thought to be exclusive to serovars Typhi and Paratyphi A. Presence of β-glucuronidase in clade B isolates specifically suggests an adaptation of this clade to the vertebrate gastrointestinal environment.</p> <p>Conclusions</p> <p><it>S. enterica </it>subsp. <it>enterica </it>consists of at least two subpopulations that differ specifically in genes involved in host and tissue tropism, utilization of host specific carbon and nitrogen sources and are therefore likely to differ in ecology and transmission characteristics.</p