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Heterochromatin that depends on histone H3 lysine 9 methylation (H3K9me) renders embedded genes transcriptionally silent.sup.1-3. In the fission yeast Schizosaccharomyces pombe, H3K9me heterochromatin can be transmitted through cell division provided the counteracting demethylase Epe1 is absent.sup.4,5. Heterochromatin heritability might allow wild-type cells under certain conditions to acquire epimutations, which could influence phenotype through unstable gene silencing rather than DNA change.sup.6,7. Here we show that heterochromatin-dependent epimutants resistant to caffeine arise in fission yeast grown with threshold levels of caffeine. Isolates with unstable resistance have distinct heterochromatin islands with reduced expression of embedded genes, including some whose mutation confers caffeine resistance. Forced heterochromatin formation at implicated loci confirms that resistance results from heterochromatin-mediated silencing. Our analyses reveal that epigenetic processes promote phenotypic plasticity, letting wild-type cells adapt to unfavourable environments without genetic alteration. In some isolates, subsequent or coincident gene-amplification events augment resistance. Caffeine affects two anti-silencing factors: Epe1 is downregulated, reducing its chromatin association, and a shortened isoform of Mst2 histone acetyltransferase is expressed. Thus, heterochromatin-dependent epimutation provides a bet-hedging strategy allowing cells to adapt transiently to insults while remaining genetically wild type. Isolates with unstable caffeine resistance show cross-resistance to antifungal agents, suggesting that related heterochromatin-dependent processes may contribute to resistance of plant and human fungal pathogens to such agents. Fission yeast grown in sublethal levels of caffeine develop heterochromatin-dependent epimutations conferring unstable heritable gene silencing that conveys resistance to caffeine, while remaining genetically wild type., Author(s): Sito Torres-Garcia [sup.1] , Imtiyaz Yaseen [sup.1] , Manu Shukla [sup.1] , Pauline N. C. B. Audergon [sup.1] [sup.2] , Sharon A. White [sup.1] , Alison L. Pidoux [sup.1] [...]

Simple Summary: Triple-negative breast cancer is characterized by a lack of targetable treatment receptors and current standard of care options, such as radiation therapy and chemotherapy, are associated with acute patient toxicity. Noninvasive imaging of PD-L1, with [89Zr]-Atezolizumab-PET imaging, has the potential to identify tumors with increased susceptibility to immunotherapy. In this work, we have optimized the labeling conditions of [89Zr]-Atezolizumab and used noninvasive [89Zr]-Atezolizumab PET imaging to characterize the longitudinal changes in PD-L1 expression in TNBC treated with standard of care treatment options. The goal of this study is to understand how [89Zr]-Atezolizumab PET imaging can characterize changes in intratumoral molecular biology and how this can inform eventual response and combination therapy. Triple-negative breast cancers (TNBCs) currently have limited treatment options; however, PD-L1 is an indicator of susceptibility to immunotherapy. Currently, assessment of PD-L1 is limited to biopsy samples. These limitations may be overcome with molecular imaging. In this work, we describe chemistry development and optimization, in vitro, in vivo, and dosimetry of [89Zr]-Atezolizumab for PD-L1 imaging. Atezolizumab was conjugated to DFO and radiolabeled with 89Zr. Tumor uptake and heterogeneity in TNBC xenograft and patient-derived xenograft (PDX) mouse models were quantified following [89Zr]-Atezolizumab-PET imaging. PD-L1 expression in TNBC PDX models undergoing therapy and immunohistochemistry (IHC) was used to validate imaging. SUV from PET imaging was quantified and used to identify heterogeneity. PET/CT imaging using [89Zr]-Atezolizumab identified a significant increase in tumor:muscle SUVmean 1 and 4 days after niraparib therapy and revealed an increased trend in PD-L1 expression following other cytotoxic therapies. A preliminary dosimetry study indicated the organs that will receive a higher dose are the spleen, adrenals, kidneys, and liver. [89Zr]-Atezolizumab PET/CT imaging reveals potential for the noninvasive detection of PD-L1-positive TNBC tumors and allows for quantitative and longitudinal assessment. This has potential significance for understanding tumor heterogeneity and monitoring early expression changes in PD-L1 induced by therapy. [ABSTRACT FROM AUTHOR]

With the changing demographics of the American workforce, the National Science Foundation, along with the U.S. Department of Commerce, has highlighted the shortage of minorities in information technology (IT) careers (http://www.ta.doc.gov/Reports/itsw/itsw.pdf). Using data from a 6-year period and the psychology Involvement-Regimen-Self Management-Social (IRSS) network theory as defined by Boice (1992), we discuss lessons learned from mentoring a group of Information Systems doctoral students who are members of a pipeline that can potentially increase the number of underrepresented faculty in business schools and who made conscious decisions to renounce the IT corporate domain. While our lessons speak to the need for more diversity awareness, we conclude that effective mentoring for underrepresented groups can and should include faculty of color (though limited in numbers) as well as majority faculty who are receptive to the needs and cultural differences of these student groups. Lastly, we draw on the work of "Ethnic America" to provide additional insight into our findings that are not offered by IRSS network theory.

Background: Survivorship care plans (SCPs) communicate cancer‐related information from oncology providers to patients and primary care providers. SCPs may limit overuse testing by specifying necessary follow‐up care. From a randomized, controlled trial of SCP delivery, we examined whether cancer‐related tests not specified in SCPs, but conducted after SCP receipt, were appropriate or consistent with overuse. Methods: Survivors of breast, colorectal, or prostate cancer treated at urban‐academic or rural‐community health systems were randomized to one of three SCP delivery arms. Tests during 18 months after SCP receipt were classified as consistent with overuse if they were (1) not included in SCPs and (2) on a guideline‐based predetermined list of "not recommended surveillance." After chart abstraction, physicians performed review and adjudication of potential overuse. Descriptive analyses were conducted of tests consistent with overuse. Negative binomial regression models determined if testing consistent with overuse differed across study arms. Results: Among 316 patients (137 breast, 67 colorectal, 112 prostate), 140 individual tests were identified as potential overuse. Upon review, 98 were deemed to be consistent with overuse: 78 tumor markers and 20 imaging tests. The majority of overuse testing was breast cancer‐related (95%). Across sites, 27 patients (9%) received ≥1 test consistent with overuse; most were breast cancer patients (22/27). Exploratory analyses of overuse test frequency by study arm showed no significant difference. Conclusions: This analysis identified practice patterns consistent with overuse of surveillance testing and can inform efforts to improve guideline‐concordant care. Future interventions may include individual practice patterns and provider education. [ABSTRACT FROM AUTHOR]

Objective: In rheumatoid arthritis (RA), anti–citrullinated protein antibodies (ACPA) can be elevated prior to inflammatory arthritis (IA). The potential to intervene in people with ACPA positivity underpins the development of prevention trials in RA. The Research Participation Influences Study examined factors influencing the decisions of individuals who are ACPA(+) to participate in a prevention trial using qualitative and quantitative methods. Methods: Individuals with ACPA positivity without IA were provided information regarding their risk for future RA, were provided a description of a clinical prevention trial using hydroxychloroquine, and were asked if they would participate in the trial. After agreeing to or declining participation, they were surveyed on what influenced their decision using Likert scales and open‐response questions. Results: Thirty‐nine individuals who agreed to trial participation (enrollees) and 31 individuals who declined (nonenrollees) completed surveys. Enrollees expressed greater perceived risk for RA and greater perception of benefit to themselves or others than nonenrollees. Nonenrollees expressed greater concern about medication effects and less personal or family experience with RA than enrollees. There was a higher proportion of first‐degree relatives (FDRs) of people with RA in enrollees versus nonenrollees (54% vs. 23%, P = 0.01). Conclusion: Enrollees were more likely than nonenrollees to be FDRs, exhibit stronger concern for personal risk for RA, and have less concern about adverse effects. Further exploration is needed to determine why these differences were present, including exploration of symptoms and the role of family history. Understanding these issues will better inform researchers and individuals who are candidates for prevention. [ABSTRACT FROM AUTHOR]

Reviews past five years of professional literature on adolescent sexuality to determine factors that influence adolescent sexuality. Discusses importance of family and religion on sexual attitudes and behaviors, how sexual activity is related to other age-related behaviors and delinquency, relationship between early coital behaviors and risk of pregnancy and sexually transmitted disease, and attitudes toward contraception and abstinence. (Author/NB)

Amyloidosis is a group of rare progressive diseases that occur as a result of abnormal protein folding and aggregation. Systemic amyloidosis is a serious disease with high mortality, and prompt diagnosis is key to improving prognosis. Conversely, localised amyloidosis does not reduce life expectancy and can often be treated with simple surgical excision. Amyloid deposits can be found in the oral cavity, usually in the context of systemic amyloidosis. We present two cases of localised oral acquired immunoglobulin light chain (AL) amyloidosis that were detected in oral biopsies taken for the management of oral epithelial dysplasia (OED). Both patients underwent thorough multisystem investigations by haematology in conjunction with the NHS National Amyloidosis Centre (NAC) in order to exclude systemic amyloidosis and confirm the diagnosis. Localised oral amyloidosis is rare, and to our knowledge, localised oral AL amyloidosis has not been reported in the context of OED before. We discuss important learning points from these cases as well as hypothesising on the pathophysiology involved. [ABSTRACT FROM AUTHOR]

Background: Survivorship care plans seek to improve the transition to survivorship, but the required resources present implementation barriers. This randomized controlled trial aimed to identify the simplest, most effective approach for survivorship care planning.Methods: Stage 1-3 breast, colorectal, and prostate cancer patients aged 21 years or older completing treatment were recruited from an urban-academic and rural-community cancer center. Participants were randomly assigned, stratified by recruitment site and cancer type 1:1:1 to a mailed plan, plan delivered during a 1-time transition visit, or plan delivered during a transition visit plus 6-month follow-up visit. Health service use data were collected from participants and medical records for 18 months. The primary outcome, receipt of all plan-recommended care, was compared across intervention arms using logistic regression adjusting for cancer type and recruitment site, with P less than .05 considered statistically significant.Results: Of 378 participants randomly assigned, 159 (42.1%) were breast, 142 (37.6%) prostate, and 77 (20.4%) colorectal cancer survivors; 207 (54.8%) from the academic site and 171 (45.2%) from the community site; 316 were analyzable for the primary outcome. There was no difference across arms in the proportion of participants receiving all plan-recommended care: 45.2% mail, 50.5% 1-visit, 42.7% 2-visit (2-sided P = .60). Adherence by cancer type for mail, 1-visit, and 2-visit, respectively, was 52.2%, 53.3%, and 40.0% for breast cancer; 48.6%, 64.1%, and 57.1% for prostate cancer; and 23.8%, 19.0%, and 26.1% for colorectal cancer. There were no statistically significant interactions by recruitment site or cancer type.Conclusions: This study did not find differences in receipt of recommended follow-up care by plan delivery approach. Feasibility and other factors may determine the best approach for survivorship care planning. [ABSTRACT FROM AUTHOR]

Research conducted on pregnant and non-pregnant adolescents showed that the ability for goal orientation among non-parenting students is similar to that of the 'at risk' students. One of the major differences between the two types were that non-parenting adolescents were more interested in intrapersonal goals than their counterparts, the 'at risk' students, or those who are likely to become failures in life. The GRADS is a program that helps teen parents and their children endure negative consequences, thereby helping them to develop positive goal orientation.

Pregnancy and sexually transmitted diseases among adolescents is considered a major problem in our society. The purpose of this study is to review the past five years of professional literature on adolescent sexuality to determine the factors which influence this social phenomenon as well as effective interventions. The importance of the family and religion on sexual attitudes and behaviors, how sexual activity is related to other age-related behaviors and delinquency, the relationship between early coital behaviors and the risk of pregnancy and sexually transmitted diseases, and attitudes toward contraception and abstinence are discussed. Also addressed are the possible psychological effects of sexual activity on the development of the adolescent.

Background/Aim: Machine learning analyses of cancer outcomes for oral cancer remain sparse compared to other types of cancer like breast or lung. The purpose of the present study was to compare the performance of machine learning algorithms in the prediction of global, recurrence‐free five‐year survival in oral cancer patients based on clinical and histopathological data. Methods: Data were gathered retrospectively from 416 patients with oral squamous cell carcinoma. The data set was divided into training and test data set (75:25 split). Training performance of five machine learning algorithms (Logistic regression, K‐nearest neighbours, Naïve Bayes, Decision tree and Random forest classifiers) for prediction was assessed by k‐fold cross‐validation. Variables used in the machine learning models were age, sex, pain symptoms, grade of lesion, lymphovascular invasion, extracapsular extension, perineural invasion, bone invasion and type of treatment. Variable importance was assessed and model performance on the testing data was assessed using receiver operating characteristic curves, accuracy, sensitivity, specificity and F1 score. Results: The best performing model was the Decision tree classifier, followed by the Logistic Regression model (accuracy 76% and 60%, respectively). The Naïve Bayes model did not display any predictive value with 0% specificity. Conclusions: Machine learning presents a promising and accessible toolset for improving prediction of oral cancer outcomes. Our findings add to a growing body of evidence that Decision tree models are useful in models in predicting OSCC outcomes. We would advise that future similar studies explore a variety of machine learning models including Logistic regression to help evaluate model performance. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.05.004 Byline: Elizabeth H. Bayne (1), Sharon A. White (1), Robin C. Allshire (1) Abstract: In fission yeast, RNA interference (RNAi)-dependent heterochromatin formation silences transgenes inserted at centromeres. In this issue, demonstrate that the RNAi machinery directly targets transgene transcripts. Furthermore, they link transgene silencing to a protein complex resembling the TRAMP complex of budding yeast, which promotes transcript degradation via the exosome. Thus, RNAi-independent transcript degradation may also contribute to heterochromatin gene silencing. Author Affiliation: (1) Wellcome Trust Centre for Cell Biology, University of Edinburgh, Kings Buildings, Michael Swann Building, Mayfield Road, Edinburgh, EH9 3JR, UK

Key Clinical Message: This case report aims to increase awareness that lichen nitidus may affect the mouth and therefore supports multidisciplinary management, particularly between dermatologists and dental professionals. [ABSTRACT FROM AUTHOR]

Accurate gain control of PET detectors is a prerequisite for quantitative accuracy. A shift in the 511 keV peak position can lead to errors in scatter correction, degrading quantitation. The PET detectors in a PET/MR scanner are subject to thermal transients due to eddy currents induced during gradient-intensive MRI sequences. Since the gain of silicon photomultiplier-based detectors changes with temperature, good gain control is particularly challenging. In this paper we describe a method that utilizes information from the entire singles spectrum to create a real-time gain control method that maintains gain of PET detectors stable within approximately ±0.5% (±2.5 keV) with varying levels of scatter and in the presence of significant thermal transients. We describe the methods used to combine information about multiple peaks and how this algorithm is implemented in a way that permits real-time processing on a field-programmable gate array. Simulations demonstrate rapid response time and stability. A method (“virtual scatter filter”) is also described that extracts unscattered photopeak events from phantom data and demonstrates the accuracy of the photopeak for various radionuclides that emit energies in addition to the pure 511 keV annihilation peak. Radionuclides 52 Mn, 55 Co, 64 Cu, 89 Zr, 90 Y, and 124 I are included in the study for their various forms of spectral contamination. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to characterise the incidence and prognostic correlation of perineural invasion (PNI) in oral squamous cell carcinoma and determine whether nerve growth factor and its receptor tyrosine Kinase A expression could be used as biological markers for PNI. Methods: A retrospective review of pathology reports of 430 patients with oral squamous cell carcinoma who were treated from 1992 to 2014 in Tayside, Scotland, was carried out. The expression of nerve growth factor and tyrosine kinase A was assessed with immunohistochemistry in 132 tissue sections of oral squamous cell carcinoma. Results: Perineural invasion was identified in 17.4% of oral squamous cell carcinomas. High expression of nerve growth factor and tyrosine kinase A was seen in 84% and 92% of oral squamous cell carcinoma, respectively. Tumours with PNI expressed nerve growth factor and tyrosine kinase A with a greater frequency than tumours without PNI. PNI and high expression of nerve growth factor were significantly associated with pain. PNI was significantly associated with stage IV tumours and poor disease‐specific survival. Conclusions: A higher level of expression of nerve growth factor and tyrosine kinase A may predict PNI and therefore may be considered as biological markers for PNI in oral squamous cell carcinoma. PNI and nerve growth factor overexpression may contribute to the pain generation in oral cancer patients. PNI and nerve growth factor expression can predict the aggressiveness and prognosis of oral squamous cell carcinoma patients. [ABSTRACT FROM AUTHOR]

The aim of the SmoCar (Smoking in the Caribbean) study was to estimate the prevalence of smoking and the disparities in the smoking practices of three regions in the Caribbean: Jamaica, Dominican Republic, and Puerto Rico. The secondary objective was to assess the prevalence and severity of gingivitis in relation to the smoking practices. The study population comprised 1,847 (weighted N = 1,830) individuals (18 years and older) who were volunteer participants from the capitals of Jamaica, Dominican Republic, and Puerto Rico. A structured interview was used to assess the participants' smoking behaviors. The gingival index was used to determine the extent of gingival inflammation. Polytomous regression was used to estimate the adjusted odds ratios (aORs) for smoking status (current, past, or never), according to risk factors (sex, age-group, education, marital status, tooth-brushing frequency, and city of residence). Logistic regression models were used to assess the associations between different smoking status variables and mild to moderate/severe gingivitis. The majority of the participants were never-smokers, with current smokers being found most commonly in Kingston (33.22%), followed by San Juan (12.76%) and Santo Domingo (8.8%). Both current (aOR = 2.22, 95% confidence interval [1.45, 3.40]) and past (aOR = 1.87, 95% confidence interval [1.19, 2.93]) smoking (vs. never smoking) was strongly associated with severe gingivitis. Smoking was the most prevalent in Jamaicans and the least prevalent in Dominicans. The study population of current smokers was found to have a fourfold increased risk of severe gingivitis and a twofold increased risk of moderate gingivitis. [ABSTRACT FROM AUTHOR]