Epigenetically silenced apoptosis-associated tyrosine kinase (AATK) facilitates a decreased expression of Cyclin D1 and WEE1, phosphorylates TP53 and reduces cell proliferation in a kinase-dependent manner.

Silencing of the Apoptosis associated Tyrosine Kinase gene (AATK) has been described in cancer. In our study, we specifically investigated the epigenetic inactivation of AATK in pancreatic adenocarcinoma, lower grade glioma, lung, breast, head, and neck cancer. The resulting loss of AATK correlates with impaired patient survival. Inhibition of DNA methyltransferases (DNMTs) reactivated AATK in glioblastoma and pancreatic cancer. In contrast, epigenetic targeting via the CRISPR/dCas9 system with either EZH2 or DNMT3A inhibited the expression of AATK. Via large-scale kinomic profiling and kinase assays, we demonstrate that AATK acts a Ser/Thr kinase that phosphorylates TP53 at Ser366. Furthermore, whole transcriptome analyses and mass spectrometry associate AATK expression with the GO term 'regulation of cell proliferation'. The kinase activity of AATK in comparison to the kinase-dead mutant mediates a decreased expression of the key cell cycle regulators Cyclin D1 and WEE1. Moreover, growth suppression through AATK relies on its kinase activity. In conclusion, the Ser/Thr kinase AATK represses growth and phosphorylates TP53. Furthermore, expression of AATK was correlated with a better patient survival for different cancer entities. This data suggests that AATK acts as an epigenetically inactivated tumor suppressor gene.

Acceptability and Efficacy of the SMARxT Media Literacy Education Program to Counter Pharmaceutical Marketing Influences among Medical Trainees.

Background: Evidence-based prescribing (EBP) results in decreased morbidity and reduces medical costs. However, pharmaceutical marketing influences medication requests and prescribing habits, which can detract from EBP. Media literacy, which teaches critical thinking, is a promising approach for buffering marketing influences and encouraging EBP. The authors developed the "SMARxT" media literacy education program around marketing influences on EBP decision-making. The program consisted of six videos and knowledge assessments that were delivered as an online educational intervention through the Qualtrics platform. Methods: In 2017, we assessed program feasibility, acceptability, and efficacy of enhancing knowledge among resident physicians at the University of Pittsburgh. Resident physicians (n=73) responded to pre-test items assessing prior knowledge, viewed six SMARxT videos, and responded to post-test items. A 6-month follow-up test was completed to quantitatively assess sustained changes in knowledge and to qualitatively assess summative feedback about the program (n=54). Test scores were assessed from pre- to post-test and from pre-test to follow-up using paired-sample t-tests. Qualitative results were synthesized through content analysis. Results: Proportion of correct knowledge responses increased from pre-test to immediate post-test (31% to 64%, P<0.001) at baseline. Correct responses also increased from pre-test to 6-month follow-up (31% to 43%, P<0.001). Feasibility was demonstrated by 95% of enrolled participants completing all baseline procedures and 70% completing 6-month follow-up. Quantitative measures of acceptability yielded positive scores and qualitative responses indicated participants' increased confidence in understanding and countering marketing influences due to the intervention. However, participants stated they would prefer shorter videos, feedback about test scores, and additional resources to reinforce learning objectives. Conclusion: The SMARxT media literacy program was efficacious and acceptable to resident physicians. Participant suggestions could be incorporated into a subsequent version of SMARxT and inform similar clinical education programs. Future research should assess program impact on real-world prescribing practices.

Vape Shop Proliferation and Noncompliance in Pennsylvania: A Pre- and Post-tax Analysis.

BACKGROUND: The growing use of electronic nicotine delivery systems (ENDS) among adolescents is a public health concern. Taxation of these products is a viable approach to reduce ENDS use, particularly among adolescents. Opponents of taxation posit that it puts specialty retailers (ie, vape shops) out of business, thereby reducing availability of ENDS for adult smokers seeking harm reduction. Pennsylvania enacted substantial ENDS taxes in October 2016. This study sought to examine (1) the prevalence of Pennsylvania vape shops before and after ENDS taxes were enacted and (2) ENDS retail licensing compliance among vape shops. METHODS: We employed standardized searches for vape shops in Pennsylvania on the Yelp business-listing platform a month prior to and for 18 consecutive months following the imposition of ENDS taxes. We then compared listings to a public database of ENDS-related retail licenses to determine compliance status. RESULTS: The number of listed vape shops increased in a linear fashion by a magnitude of 23%. In addition, when we compared a final listing of retailers to data from the state tax authority, we found roughly a quarter (22%-29%) of vape shops to be noncompliant with maintaining a valid ENDS retail license. CONCLUSIONS: Overall, ENDS taxation in Pennsylvania has not appeared to reduce prevalence of vape shops as anticipated. However, stricter enforcement of the tax law is necessary to ensure compliance among retailers. These findings have implications for implementation and enforcement of ENDS tax policy nationwide, including states that currently lack such policies.

RASSF10 is frequently epigenetically inactivated in kidney cancer and its knockout promotes neoplasia in cancer prone mice.

Kidney cancer incidences are rising globally, thereby fueling the demand for targeted therapies and precision medicine. In our previous work, we have identified and characterized the Ras-Association Domain Family encoding ten members that are often aberrantly expressed in human cancers. In this study, we created and analyzed the Rassf10 knockout mice. Here we show that Rassf10 haploinsufficiency promotes neoplasia formation in two established mouse cancer models (Rassf1A-/- and p53-/-). Haploinsufficient Rassf10 knockout mice were significantly prone to various diseases including lymphoma (Rassf1A-/- background) and thymoma (p53-/- background). Especially Rassf10-/- and p53-deficient mice exhibited threefold increased rates of kidney cysts compared with p53-/- controls. Moreover, we observed that in human kidney cancer, RASSF10 is frequently epigenetically inactivated by its CpG island promoter hypermethylation. Primary tumors of renal clear cell and papillary cell carcinoma confirmed that RASSF10 methylation is associated with decreased expression in comparison to normal kidney tissue. In independent data sets, we could validate that RASSF10 inactivation clinically correlated with decreased survival and with progressed disease state of kidney cancer patients and polycystic kidney size. Functionally, we revealed that the loss of Rassf10 was significantly associated with upregulation of KRAS signaling and MYC expression. In summary, we could show that Rassf10 functions as a haploinsufficient tumor suppressor. In combination with other markers, RASSF10 silencing can serve as diagnostic and prognostic cancer biomarker in kidney diseases.

RASSF10 Is a TGFß-Target That Regulates ASPP2 and E-Cadherin Expression and Acts as Tumor Suppressor That Is Epigenetically Downregulated in Advanced Cancer.

The Ras Association Domain Family (RASSF) encodes members of tumor suppressor genes which are frequently inactivated in human cancers. Here, the function and the regulation of RASSF10, that contains a RA (Ras-association) and two coiled domains, was investigated. We utilized mass spectrometry and immuno-precipitation to identify interaction partners of RASSF10. Additionally, we analyzed the up- and downstream pathways of RASSF10 that are involved in its tumor suppressive function. We report that RASSF10 binds ASPP1 (Apoptosis-stimulating protein of p53) and ASPP2 through its coiled-coils. Induction of RASSF10 leads to increased protein levels of ASPP2 and acts negatively on cell cycle progression. Interestingly, we found that RASSF10 is a target of the EMT (epithelial mesenchymal transition) driver TGFß (Transforming growth factor beta) and that negatively associated genes of RASSF10 are significantly over-represented in an EMT gene set collection. We observed a positive correlation of RASSF10 expression and E-cadherin that prevents EMT. Depletion of RASSF10 by CRISPR/Cas9 technology induces the ability of lung cancer cells to proliferate and to invade an extracellular matrix after TGFß treatment. Additionally, knockdown of RASSF10 or ASPP2 induced constitutive phosphorylation of SMAD2 (Smad family member 2). Moreover, we found that epigenetic reduction of RASSF10 levels correlates with tumor progression and poor survival in human cancers. Our study indicates that RASSF10 acts a TGFß target gene and negatively regulates cell growth and invasion through ASPP2. This data suggests that epigenetic loss of RASSF10 contributes to tumorigenesis by promoting EMT induced by TGFß.

Use of fictional medical television in health sciences education: a systematic review.

While medical television programs are popular among health profession trainees, it is not clear to what extent these programs affect their knowledge, perceptions, and/or behaviors. Therefore, we conducted a systematic review of research evaluating associations between program exposure and outcomes. We conducted systematic literature searches in Pubmed, CINAHL, and PsycINFO. Selected studies were required to be scholarly research, involve exposure to fictionalized medical television programming by health professional students, and assess associations between exposure and outcomes. Studies were classified according to quality and factors related to population, exposure, and outcomes. Of 3541 studies identified, 13 met selection criteria. Six studies involved undergraduate medical students, one involved nursing students, two involved both medical and nursing students, two involved medical residents, one involved medical students, residents and attending physicians, and one involved graduate epidemiology students. Mean study quality according to the MERSQI was 8.27. The most commonly assessed television programs were ER and Grey's Anatomy (six each). Five studies assessed regular viewing habits, and found that fictional medical programs are popular among students and that students recall health topics from episodes. The eight studies that assessed the association with outcomes when using clips as educational tools reported high satisfaction and increased knowledge of the presented health topics. While relatively few published studies have explored influences of fictional medical television on health professional students, those conducted suggest that students often view these television programs independently and that integration of this programming into medical education is feasible and acceptable.

Impact of Natural Compounds on DNA Methylation Levels of the Tumor Suppressor Gene RASSF1A in Cancer.

Epigenetic inactivation of tumor suppressor genes (TSG) is a fundamental event in the pathogenesis of human cancer. This silencing is accomplished by aberrant chromatin modifications including DNA hypermethylation of the gene promoter. One of the most frequently hypermethylated TSG in human cancer is the Ras Association Domain Family 1A (RASSF1A) gene. Aberrant methylation of RASSF1A has been reported in melanoma, sarcoma and carcinoma of different tissues. RASSF1A hypermethylation has been correlated with tumor progression and poor prognosis. Reactivation of epigenetically silenced TSG has been suggested as a therapy in cancer treatment. In particular, natural compounds isolated from herbal extracts have been tested for their capacity to induce RASSF1A in cancer cells, through demethylation. Here, we review the treatment of cancer cells with natural supplements (e.g., methyl donors, vitamins and polyphenols) that have been utilized to revert or prevent the epigenetic silencing of RASSF1A. Moreover, we specify pathways that were involved in RASSF1A reactivation. Several of these compounds (e.g., reseveratol and curcumin) act by inhibiting the activity or expression of DNA methyltransferases and reactive RASSF1A in cancer. Thus natural compounds could serve as important agents in tumor prevention or cancer therapy. However, the exact epigenetic reactivation mechanism is still under investigation.

Preliminary Evaluation of a School-Based Youth Leadership and Prevention Program in Rural Alaska Native Communities.

Youth Leaders Program (YLP) is a health intervention implemented in a rural Alaskan school district, which utilizes natural helpers and peer leaders to increase protective factors such as school engagement and personal/cultural identities, and to reduce risks associated with drug/alcohol abuse, violence, and bullying. Through these means, the program aims to ultimately decrease the disproportionately high rates of indigenous youth suicide in the region. This paper describes process and outcome evaluation findings from the program during the 2013-2014 school year. Data collected include a survey for program participants done at the beginning and end of the study year (n = 61, complete pairs); pre- and post-intervention school data (attendance, GPA, and disciplinary actions) (n = 86); an all-school survey asking students at the participating schools about their experience with YLP and participating youth (n = 764); interviews with program advisors (n = 11) and school principals (n = 2); and focus groups with participating students at all eleven participating schools at the end of the year. Outcomes included increased school attendance (mean attendance increased from 146 to 155 days) and improved academic performance (mean GPA of 8th, 9th, and 10th graders increased from 3.01 to 3.14) of program participants; positive peer reviews of participating student interventions in cases of bullying, depression, and suicidality; and a reported increase in the sense of agency, responsibility, and confidence among participating youth. The YLP appears to improve school climate and increase school and other protective factors for participating students. Recommendations for program implementation in the future and implications for school health will be discussed.

Australian Nurse Practitioner Practice: Value Adding through Clinical Reflexivity.

The role of the Australian Nurse Practitioner (NP) is in its infancy and at a crossroads where extensive research demonstrates effective quality care and yet the role remains underrecognised and underutilised. The translation of practice into "value" is critical for the sustainability of NP roles and requires the practitioner to adopt a systematic method of inquiry. Kim's (1999) "Critical Reflective Inquiry" (CRI) method was adapted by two Australian NPs who specialise in diabetes and chronic disease management. Kim highlights the intent of CRI as understanding the meaning of practice, delivering improvements to practice through self-reflection, and the critique of practice that can lead to practice changes and development of new models of care translated to "products" of value. Based on the thematically analysis of 3 years of CRI application, the authors formed 5 headings that represented the NP's practice as Specialised Care Access, Complications and Diagnostics Interventions, Pharmaceutical Treatment, Vulnerable Populations, and Leadership. The utility of CRI demonstrates how NP practice is integral to a continuous cycle of addressing health care services gaps, and the conversion of "products" into "value" and positions the NP to assimilate the role of the practitioner-researcher.

Public health intervention model: impact on Australian community and mental health nursing students' practice.

Recent Australian health care reform in all jurisdictions of government, have attempted to address the need to curtail the burden of chronic disease by adopting and or referring to a primary health care (PHC) approach. In this way, community health nurses are challenged to demonstrate their understanding and capacity to practice according to primary health care principles. Evaluated in this paper is the impact a community health nursing curriculum adaptation of the Public Health Intervention Model (PHIM) has had on students' understanding and application of PHC to community nursing practice. A thematic analysis was utilized to review student assessment tasks. Generated themes support the PHIM adaptation, as a means to facilitate students' cognitive learning of community nursing practice interventions 'greater than treating the wound', and thus this model is particularly pertinent to future Bachelor of Nursing curriculum development and Australian Community Health Nursing.

Experiential learning driving community based nursing curriculum.

CONTEXT: The School of Nursing and Midwifery at the University of Tasmania, Australia, is the only bachelor of nursing provider in the State of Tasmania. This arrangement is unique among Australian states, which all have multiple providers. In Tasmania's situation, community based nursing students are dispersed for their clinical practica across metropolitan, urban, rural and remote clinical nursing practice. The range of practice is also diverse, and students may be exposed to the span of community health experience, from adolescent, child and family health to specialist clinics in wound care, asthma or diabetes. ISSUES: Providing a curriculum that meets the requirements of the course registering authority as well as the individual clinical learning requirements is challenging. Authentic learning in a diverse context and dispersed venues is difficult to ensure. However the intent to improve the health status of the population served through community practice nursing interventions, guided by primary health care principles, is common to all clinical placements. A curriculum designed to standardise community health practice experience and theory may not address students' learning needs in any of the practice areas. These challenges have been addressed in an experiential learning approach that focuses on the needs of the learner. LESSONS LEARNED: The fundamental principles that hold the diverse curriculum together are: (1) the experiential focus; and (2) the partnership developed between the university and the facility that supports both students and facilitator/preceptors. Providing rural and remote student practicum experiences enhances the learning outcomes of the student and the health outcomes of the community. It encourages the consideration of rural and remote community based nursing practice as a viable professional option for graduates.

Impaired gastrocolonic response and peristaltic reflex in slow-transit constipation: role of 5-HT(3) pathways.

Colonic motility is modulated by the 5-hydroxytryptamine (5-HT)(3)-dependent gastrocolonic response and 5-HT(3)-independent peristaltic reflex. We compared descending colon tone responses to antral distension, duodenal lipid perfusion, and colonic distension after double-blind placebo or granisetron in 13 healthy volunteers and nine slow-transit constipated patients. Antral distension (100-300 ml) and duodenal lipids (3 kcal/min) evoked increases in colon tone in volunteers, which were blunted in constipated patients (P < 0.05). Granisetron (10 microg/kg) reduced responses to antral distension and lipids in volunteers and to lipids in constipated patients (P < 0.05). The ascending contraction of the peristaltic reflex was blunted in constipated patients (P < 0.05), whereas descending responses were similar. Granisetron did not modify the peristaltic reflex. Colonic responses to bethanechol were similar in patients and volunteers. In conclusion, antral distension- and duodenal lipid-activated gastrocolonic responses and ascending contractions of the peristaltic reflex are impaired with slow-transit constipation with loss of both 5-HT(3)-dependent and -independent function. Thus abnormalities of neural reflex modulation of colonic motor function may play pathophysiological roles in slow-transit constipation.