Awareness and interest in lung cancer screening among current and former smokers: findings from the ITC United States Survey.

PURPOSE: To examine the awareness of low-dose computed tomography (LDCT) lung cancer screening among a population of current and former smokers using a nationally representative sample from the United States. METHODS: Data for this study come from Wave 9 of the International Tobacco Control (ITC) United States Survey, conducted between 2013 and 2015. Among respondents age ≥ 40 (n = 1145), a 50% random sample were asked a series of questions pertaining to lung cancer screening. This study examines awareness and screening behaviors in relationship to demographic characteristics of respondents, health beliefs, psychosocial behaviors, and smoking behaviors. Descriptive tables and χ2 tests were used to examine the association between those who were aware and unaware. Logistic regression analyses were conducted, stratified on respondents' smoking status. Data were weighed to be representative of the current smoking population in the US. RESULTS: Overall, 52% of current and former smokers reported being aware of lung cancer screening. Among the group with no prior screening, 80.6% said they would take a lung cancer screening exam if recommended by their physician. In the multivariate models, former smokers had significantly greater awareness of lung cancer screening compared to current smokers [odds ratio 1.42 (95% confidence interval 1.03, 1.97)]. CONCLUSIONS: Awareness of LDCT lung cancer screening was lower among current smokers compared to former smokers. Most smokers who had not ever been screened said they would have lung cancer screening if it were recommended by their physician, demonstrating the need for healthcare providers to encourage those eligible for screening to take the test.

Focus Groups and In-depth Interviews to Guide the Development of Lung Cancer Screening Informational Materials.

Lung cancer is one of the most lethal cancers in the USA. In 2013, new guidelines issued by the United States Preventive Services Task Force recommended lung cancer screening using low-dose computed tomography among a selected group of high-risk individuals. Specifically, lung cancer screening is recommended for heavy smokers between the ages of 55 to 79, with at least 30 pack-year smoking exposure. Former smokers who meet these guidelines and stopped smoking ≤ 15 years ago are also eligible. There is a need to promote lung cancer screening to increase early diagnosis rates and treatment options, thereby decreasing disease-specific mortality. This study was conducted to refine educational materials used to inform eligible high-risk individuals about the risks and benefits of lung cancer screening. Focus groups (n = 16) and in-depth telephone interviews (n = 5) were conducted among screening-eligible participants recruited from western New York. Main themes that emerged from the discussions included cost of obtaining the exam, eligibility criteria/information about the exam, apprehension regarding results, and an increased desire for discussions with their physician to learn more about the screening. The information gained from this study is vital to understanding concerns held by current and former smokers regarding lung cancer screening, as well as critical to determining which information is most valuable for decreasing barriers and correcting misperceptions about the lung cancer screening exam.

Situational and Demographic Factors in the Sudden Growth of Pall Mall, 2002-2014.

Objective: Pall Mall gained significant brand share in the cigarette market between 2002 and 2013. We sought to determine whether demographic shifts occurred among the participants reporting Pall Mall as their usual brand during this time span. Method: We examined National Survey of Drug Use and Health (NSDUH) data from 2002-2014. Demographic characteristics included age, education, ethnicity, income, and cigarette use (cigarettes per day, daily/non-daily smoking, and nicotine dependence). We also examined RJ Reynolds investor reports and shareholder documents to determine the impact of tobacco marketing on the growth of Pall Mall. Results: Over 2002-2014, Pall Mall has gained among smokers 26 to 34 years of age. More Pall Mall smokers in 2014 report higher incomes (over $75000), and also report lower scores on measures of cigarette dependence, compared to 2002. Pall Mall smokers over time seem to share characteristics of premium cigarette brands smokers. Conclusion: The profile of the typical Pall Mall smoker has changed as the brand has gained market share. An association exists between brand positioning and economic forces, which has contributed to an increase in the market share for Pall Mall. Implications: It is well known that cigarette marketing drives the sale of tobacco products. The growth in the market share of Pall Mall serves as an excellent example to demonstrate how economic uncertainty paired with brand positioning and advertising worked together to serve as a catalyst for the rapid growth observed for this brand. This paper also looked at various demographic changes that occurred among Pall Mall smokers over a 12 year period and compared them to smokers of all other cigarette brands. The results of this analysis demonstrate the importance of monitoring trends over time among cigarette smokers.

Does marriage explain murders in a society? In what way is divorce a public health concern?

INTRODUCTION: Like medicine, public health practitioners seek to understand causes of mortality, practices of humans and issues that can change population conditions, in order to preserve and care for life. The murder pandemic has been such in Jamaica that the World Bank sponsored a qualitative study on crime in urban areas in Jamaica in the late 1990s to provide a platform to guide policy intervention and programmes. As a result this study will fill the gap in the literature by providing the evidence to support that divorce and marriage are public health concerns from the perspective of murders. OBJECTIVE: To evaluate the role of divorce and marital relationships on murders. MATERIALS AND METHODS: The data for this study are taken from various Jamaica Government Publications. The period for this work is from 1950 through 2013. Data were recorded, stored and retrieved using the Statistical Packages for the Social Sciences (SPSS) for Windows, Version 21.0. The level of significance that is used to determine statistical significance is less than 5% (0.05). Ordinary least square (OLS) regression analyses and curve estimations were used to determine models and best fitted models. RESULTS: On average, annually, 523 Jamaicans are murdered (± 484), with there being 9,531 marriages (± 22,747) and 904 divorces (± 468). Logged marriage rate and divorce rate are factors of murder rate, with both independent factors accounting for 82.2% of the variability in the murder rate. Both factors are positively correlated with the murder rate, with the divorce rate accounting for most of the variance in the murder rate (R2 = 79.2%). CONCLUSION: Death can be extremely devasting to families, however, murder among married couples can severely disrupt the lives of both families along with any children from such relationship.

Diversity and Representation Among United States Participants in Amgen Clinical Trials.

OBJECTIVE: Describe the demographic profile of US participants in Amgen clinical trials over a 10-year period and variations across therapeutic areas, indications, and geographies. METHODS: Cross-sectional retrospective study including participants enrolled (2005-2020) in phase 1-3 trials completed between January 1, 2012 and June 30, 2021. RESULTS: Among 31,619 participants enrolled across 258 trials, one-fifth represented racial minority populations (Asian, 3%; Black or African American, 17%; American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, multiracial, each < 1%); fewer than one-fifth (16%) represented an ethnic minority population (Hispanic or Latino). Compared with census data, representation of racial and ethnic groups varied across US states. Across most therapeutic areas (bone, cardiovascular, hematology/oncology, inflammation, metabolic disorders, neuroscience) except nephrology, participants were predominantly White (72-81%). A similar proportion of males and females were enrolled between 2005 and 2016; male representation was disproportionately higher than female between 2016 and 2020. Across most medical indications, the majority of participants were 18-65 years of age. CONCLUSIONS AND RELEVANCE: While the clinical research community is striving to achieve diversity and proportional representation across clinical trials, certain populations remain underrepresented. Our data provide a baseline assessment of the diversity and representation of US participants in Amgen-sponsored clinical trials and add to a growing body of evidence on the importance of diversity in clinical research. These data provide a foundation for strategies aimed at supporting more equitable and representative research, and a baseline from which to assess the impact of future strategies to advance health equity.

Reversible HER2 antibody-drug conjugate-induced ocular toxicity.

PURPOSE: To report 3 cases of reversible epitheliopathy induced by A166-a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate (ADC) therapy for resistant HER2 tumours. METHODS: Advanced HER2 tumour patients were enrolled in A166 phase I/II clinical trial using Bayesian logistic regression model dose escalation. Key exclusion criteria were ≥grade 2 (G2) corneal pathology, severe organ disease, and other cancer therapy within 4 weeks. Eye exams were performed at baseline, regularly scheduled intervals, and additionally upon A166-induced ocular symptoms. Topical therapy with autologous serum tears (ASTs) was implemented based on visual acuity, symptoms, and slit lamp exam. A166 was withheld if ≥G2 ocular toxicity developed; if status improved to ≤G1, A166 therapy was resumed. Visual acuity, corneal exam, and subjective comfort were recorded. RESULTS: After ≥2 cycles of A166, 6 eyes of 3/23 enrolled patients developed whorl pattern epitheliopathy suggestive of limbal stem cell (LSC) dysfunction requiring cessation of A166 despite positive tumour response. Patients 1 and 3 received 3.6 mg/kg A166 dose, and patient 2 received 3.0 mg/kg. Topical steroids (2/4 eyes) failed to improve epitheliopathy. Adding ASTs improved vision, ocular comfort, and whorl pattern epitheliopathy in 6/6 eyes within 3 weeks. Patient 1 continues to improve on ASTs; patient 2 withdrew from the study; and patient 3 resumed A166 therapy. CONCLUSION: A166 precipitates LSC dysfunction-like epitheliopathy. Combination therapy including aggressive lubrication, withholding drug, and ASTs help reverse toxicity. Recognizing that ADC-induced epitheliopathy can respond to ocular management may enable cancer patients to continue lifesaving therapy.

Comparing smoking behavior between female-to-male and male-to-female transgender adults.

INTRODUCTION: This study aimed to assess the association between current smoking and gender identity among transgender individuals. METHODS: Data were collected using a cross-sectional survey distributed among transgender individuals attending the Houston Pride Festival and those seeking care at a local transgender health clinic. Relevant variables were compared between female-to-male (FTM) and male-to-female (MTF) transgender individuals using χ2, Fisher's exact, and two-sample t-tests, when appropriate. Gender identity was used to predict current smoking status using logistic regression, adjusting for other sociodemographic determinants. RESULTS: The study sample (N=132) comprised 72 MTF (54.5%) and 60 FTM (45.5%) transgender individuals. Mean age of participants was 31.8 years. The sample was racially and ethnically diverse: 45.8% Caucasian, 25.2% Hispanic/Latino, 16.8% African American, and 12.2% other. Current smoking prevalence was 26.7% and 13.9% among FTM and MTF individuals, respectively. Transgender individuals were more likely to self-report current smoking if they were FTM (OR=3.76; 95% CI: 1.17-12.06; p=0.026) or were insured (OR=4.49; 95% CI: 1.53-13.18; p=0.006). CONCLUSIONS: This study reports on important findings by examining intragroup differences in smoking behavior among the transgender population. However, further research is needed for tailoring smoking prevention and cessation interventions for transgender subgroups.

Physician-office vs home uptake of colorectal cancer screening using FOBT/FIT among screening-eligible US adults.

BACKGROUND: Guidelines of the American Cancer Society and US Preventive Services Task Force specify that colorectal cancer (CRC) screening using guaiac-based fecal occult blood test (FOBT)/fecal immunochemical test (FIT) should be done at home. We therefore examined the prevalence and correlates of CRC screening using FOBT/FIT in physicians' office vs at home. METHODS: Analysis of 9493 respondents 50-75 years old from the Cancer Control Supplement of the 2015 National Health Interview Survey was conducted. Weighted multivariable logistic regression was used to identify the determinants of in-office vs home use of FOBT/FIT for CRC screening. RESULTS: Of the overall sample of screening-eligible adults (n = 9403), only 937 (10.4%) respondents underwent CRC screening using FOBT/FIT within the past year; among this screening population, 279 (28.3%) respondents were screened in-office. We found that sociodemographic factors alone, not CRC risk factors, determined whether FOBT/FIT would be used in-office or at home. Hispanics had greater odds of being screened in-office using FOBT/FIT (aOR: 2.04; 95% CI: 1.05-3.99). Compared with those 50-59 years old, respondents 70-75 years old were less likely to be screened in-office using FOBT/FIT (aOR: 0.44, 95% CI: 0.25-0.79). Similarly, individuals residing in the Western region of the country had lower odds of in-office FOBT/FIT (aOR: 0.26; 95% CI: 0.11-0.58). CONCLUSION: Amid low overall uptake rates of FOBT/FIT in the United States, in-physician office testing is high, indicative of a missed opportunity for effective screening and poor adherence of physicians to national guidelines. Sociodemographic factors are determinants of uptake of FOBT/FIT at home or in-office and should be considered in designing interventions aimed at providers and the general population.

Using a Smoking Cessation Quitline to Promote Lung Cancer Screening.

Objective We assessed whether in-depth messaging delivered via a smoking cessation quitline results in participants: (1) speaking to their physician, or (2) insurance company regarding lung cancer screening (LCS). MethodsEligible participants lived in New York State and met the United States Preventive Services Task Force eligibility criteria for LCS (N = 1000). A randomized trial was conducted among New York State Smokers' Quitline participants to assess the impact of a brochure containing information on risks, benefits, and costs associated with LCS (control group) versus the brochure supplemented with phone-based in-depth messaging (treatment group). ResultsAfter a 4-month telephone survey (N = 431), associations between the study groups were examined for: (1) speaking with a physician regarding LCS, and (2) speaking with an insurance company about LCS coverage. Multivariate logistic regression models adjusted for demographics, insurance status, emphysema/COPD, and past 30-day cigarette use found no significant associations. However, sensitivity analyses among control participants found significant associations, including for speaking with a physician (p < .05) by receipt of the study brochure. Analyses repeated in the treatment group also had statistically significant findings emerge, including for speaking with insurance company (p < .05). ConclusionsThe educational brochure may be an effective and low-cost way to deliver information about LCS.

Vortex Pattern of Corneal Deposits in Granular Corneal Dystrophy Associated With the p.(Arg555Trp) Mutation in TGFBI.

PURPOSE: To describe 2 unrelated families with multiple members demonstrating a less commonly recognized vortex pattern of corneal deposits confirmed to be granular corneal dystrophy type 1 (GCD1) after identification of the p.(Arg555Trp) mutation in the transforming growth factor ß-induced gene (TGFBI). METHODS: A slit-lamp examination was performed on individuals from 2 families, one of Mexican descent and a second of Italian descent. After DNA extraction from affected individuals and their unaffected relatives, TGFBI screening was performed. RESULTS: Eight of 20 individuals in the Mexican family and 20 of 55 in the Italian family demonstrated corneal stromal opacities. Seven of the 8 affected individuals in the Mexican family and 4 of the 20 affected individuals in the Italian family demonstrated a phenotype characterized by a "sea fan" or vortex pattern of superficial stromal corneal deposits originating from the inferior aspect of the cornea. Screening of TGFBI in both families revealed a heterozygous missense mutation [p.(Arg555Trp)] in exon 12, confirming the diagnosis of GCD1. CONCLUSIONS: Our findings demonstrate that GCD1 may present with a vortex pattern of anterior stromal deposits. Although this pattern of dystrophic deposits is not recognized by clinicians as a typical phenotype of GCD1, it is consistent with the production of the majority of the TGFBI protein by the corneal epithelium.

Late-onset, snowstorm-like appearance of calcium deposits coating a poly(methyl methacrylate) posterior chamber intraocular lens.

UNLABELLED: An 81-year-old man developed decreased vision associated with diffuse precipitates on his poly(methyl methacrylate) (PMMA) posterior chamber intraocular lens (IOL), on his corneal endothelium, and in his anterior chamber approximately 35 years after IOL implantation. Slitlamp evaluation showed diffuse white material on the surface of the IOL, white precipitates on the corneal endothelium, and visible debris in the anterior chamber. The patient had IOL exchange, and pathological analysis showed numerous calcium deposits within the Soemmerring ring that diffusely spread to the anterior surface of the PMMA IOL. This case of diffuse calcium precipitates on the IOL and the corneal endothelium and in the anterior chamber 35 years after implantation shows that even long after IOL implantation, lens epithelium proliferation and metabolism can result in sequestered material that can be released many years later. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned.

Trends in market share of leading cigarette brands in the USA: national survey on drug use and health 2002-2013.

OBJECTIVES: The main objective of this study is to examine trends in market share for leading cigarette brands, both before (2002-2008) and after (2009-2013) Food and Drug Administration (FDA) regulation of tobacco products.Design Data come from the annual National Survey on Drug Use and Health from 2002 through 2013. Descriptive statistics, cross tabulations, and logistic regression were employed. Data were weighted to the US population and adjusted for cigarette consumption. Our analysis is restricted to 164,343 current cigarette smokers who were at least 12 years of age or older, had smoked at least one cigarette in the 30 days prior to the survey, and reported a usual cigarette brand at the time of the survey. RESULTS: Over 12 years, 14 brands comprised over 77% of the cigarette market. Marlboro consistently held over 38% of the market. Newport held the second highest market share, and increased from 7.2% in 2002 to 10.9% by 2013. Market share of Pall Mall grew by over 400% (1.7% in 2002 vs 8.9% in 2013), likely aided by the 2009 Federal excise tax increase. No clear associations of changes in market share with the implementation of FDA's regulatory authority over tobacco in 2009 were noted. CONCLUSIONS: Tracking market share trends offers clues about brand marketing changing preferences of consumers. Rapidly growing cigarette brands should be monitored to determine if specific marketing practices or design changes are drivers, as these could represent public health concerns. Monitoring trends in cigarette market share could inform regulatory decision-making efforts related to marketing and advertising.

Development of a nomogram for femtosecond laser astigmatic keratotomy for astigmatism after keratoplasty.

PURPOSE: To develop a nomogram for femtosecond laser astigmatic keratotomy (AK) to treat post-keratoplasty astigmatism. SETTING: Three academic medical centers. DESIGN: Retrospective interventional case series. METHODS: A review of post-keratoplasty femtosecond laser AK was performed. Uncorrected (UDVA) and corrected (CDVA) distance visual acuities, manifest refraction, and keratometry were recorded preoperatively and 1, 3, 6, and 12 months postoperatively. The location, length, depth, and diameter of the AK incisions were recorded, and the surgically induced astigmatic correction was related to these variables using regression analysis. RESULTS: One hundred forty femtosecond laser AK procedures were performed after penetrating keratoplasty (PKP) (n = 129) or deep anterior lamellar keratoplasty (DALK) (n =11), with 89 procedures (80 PKP, 9 DALK) included in the analysis. The mean CDVA improved from 20/59 (0.47 logMAR ± 0.38 [SD]) preoperatively to 20/45 (0.35 ± 0.31 logMAR) postoperatively (P = .013) (n = 46). The mean keratometric astigmatism decreased from 8.26 ± 2.90 diopters (D) preoperatively to 3.62 ± 2.59 D postoperatively (P < .0001) (n = 89). The mean refractive cylinder decreased from 6.77 ± 2.80 D preoperatively to 2.85 ± 2.57 D postoperatively (P < .0001) (n = 69). A nomogram for femtosecond laser AK to treat post-keratoplasty astigmatism was generated using regression analysis. CONCLUSIONS: Femtosecond laser AK significantly improved UDVA and CDVA and significantly reduced keratometric astigmatism and refractive cylinder after keratoplasty. The nomogram generated should improve the accuracy of post-keratoplasty femtosecond laser AK. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned.

Aging: a predisposition to dry eyes.

Dry eye syndrome is a disease of the ocular surface and tear film that is prevalent in older adults. Even though the degree of visual acuity loss in dry eye patients is commonly mild-to-moderate, in the aging population, this minimal change in visual status can lead to a significant decrease in visual function and quality of life. A healthy ocular surface is maintained by appropriate tear production and tear drainage, and deficiencies in this delicate balance can lead to dryness. In the aging eye, risk factors such as polypharmacy, androgen deficiency, decreased blink rates, and oxidative stress can predispose the patient to developing dry eye that is frequently more severe, has higher economic costs, and leads to worse consequences to the well-being of the patient. Understanding why elderly patients are at higher risk for developing dry eyes can provide insights into the diagnosis and management of the growing number of older adults struggling with dry eye and minimize the burden of disease on our aging population.

Quantification of AgNOR expression in exfoliated oral mucosal cells of tobacco chewers with and without lesion.

BACKGROUND: Nucleolar organizer regions (NOR) are associated with proliferative activity and represent a diagnostic and prognostic marker. MATERIALS AND METHODS: Smears were taken from smokers, tobacco chewers, oral squamous cell carcinoma patients, and normal subjects and evaluated by 2 silver-staining nucleolar organizer region (AgNOR) counting methods: (1) mean number of AgNORs per nucleus (mAgNOR); and (2) percentage of nuclei with >3 and >5 AgNORs (pAgNOR). RESULTS: A statistically significant difference was observed between normal subjects, smokers, tobacco chewers, and oral cancer patients and between tobacco chewers with and without lesion. No significant difference was observed between tobacco chewers and smokers except in the percentage of >5 criteria. CONCLUSIONS: AgNOR enumeration using noninvasive methods, such as the cytobrush appears to be useful technique in distinguishing between normal mucosa, mucosa with and without lesions exposed to carcinogens, such as tobacco and frank oral carcinoma.

Evolution of a distinct genomic domain in Drosophila: comparative analysis of the dot chromosome in Drosophila melanogaster and Drosophila virilis.

The distal arm of the fourth ("dot") chromosome of Drosophila melanogaster is unusual in that it exhibits an amalgamation of heterochromatic properties (e.g., dense packaging, late replication) and euchromatic properties (e.g., gene density similar to euchromatic domains, replication during polytenization). To examine the evolution of this unusual domain, we undertook a comparative study by generating high-quality sequence data and manually curating gene models for the dot chromosome of D. virilis (Tucson strain 15010-1051.88). Our analysis shows that the dot chromosomes of D. melanogaster and D. virilis have higher repeat density, larger gene size, lower codon bias, and a higher rate of gene rearrangement compared to a reference euchromatic domain. Analysis of eight "wanderer" genes (present in a euchromatic chromosome arm in one species and on the dot chromosome in the other) shows that their characteristics are similar to other genes in the same domain, which suggests that these characteristics are features of the domain and are not required for these genes to function. Comparison of this strain of D. virilis with the strain sequenced by the Drosophila 12 Genomes Consortium (Tucson strain 15010-1051.87) indicates that most genes on the dot are under weak purifying selection. Collectively, despite the heterochromatin-like properties of this domain, genes on the dot evolve to maintain function while being responsive to changes in their local environment.

Protein kinase C regulates internal initiation of translation of the GATA-4 mRNA following vasopressin-induced hypertrophy of cardiac myocytes.

GATA-4 is a key member of the GATA family of transcription factors involved in cardiac development and growth as well as in cardiac hypertrophy and heart failure. Our previous studies suggest that GATA-4 protein synthesis may be translationally regulated. We report here that the 518-nt long 5'-untranslated region (5'-UTR) of the GATA-4 mRNA, which is predicted to form stable secondary structures (-65 kcal/mol) such as to be inhibitory to cap-dependent initiation, confers efficient translation to monocistronic reporter mRNAs in cell-free extracts. Moreover, uncapped GATA-4 5'-UTR containing monocistronic reporter mRNAs continue to be well translated while capped reporters are insensitive to the inhibition of initiation by cap-analog, suggesting a cap-independent mechanism of initiation. Utilizing a dicistronic luciferase mRNA reporter containing the GATA-4 5'-UTR within the intercistronic region, we demonstrate that this leader sequence confers functional internal ribosome entry site (IRES) activity. The activity of the GATA-4 IRES is unaffected in trans-differentiating P19CL6 cells, however, is strongly stimulated immediately following arginine-vasopressin exposure of H9c2 ventricular myocytes. IRES activity is then maintained at submaximal levels during hypertrophic growth of these cells. Supraphysiological Ca(2+) levels diminished stimulation of IRES activity immediately following exposure to vasopressin and inhibition of protein kinase C activity utilizing a pseudosubstrate peptide sequence blocked IRES activity during hypertrophy. Thus, our data suggest a mechanism for GATA-4 protein synthesis under conditions of reduced global cap-dependent translation, which is maintained at a submaximal level during hypertrophic growth and point to the regulation of GATA-4 IRES activity by sarco(ER)-reticular Ca(2+) stores and PKC.

Cyclin D1 and c-myc internal ribosome entry site (IRES)-dependent translation is regulated by AKT activity and enhanced by rapamycin through a p38 MAPK- and ERK-dependent pathway.

The macrolide antibiotic rapamycin inhibits the mammalian target of rapamycin protein (mTOR) kinase resulting in the global inhibition of cap-dependent protein synthesis, a blockade in ribosome component biosynthesis, and G1 cell cycle arrest. G1 arrest may occur by inhibiting the protein synthesis of critical factors required for cell cycle progression. Hypersensitivity to mTOR inhibitors has been demonstrated in cells having elevated levels of AKT kinase activity, whereas cells containing quiescent AKT activity are relatively resistant. Our previous data suggest that low AKT activity induces resistance by allowing continued cap-independent protein synthesis of cyclin D1 and c-Myc proteins. In support of this notion, the current study demonstrates that the human cyclin D1 mRNA 5' untranslated region contains an internal ribosome entry site (IRES) and that both this IRES and the c-myc IRES are negatively regulated by AKT activity. Furthermore, we show that cyclin D1 and c-myc IRES function is enhanced following exposure to rapamycin and requires both p38 MAPK and RAF/MEK/ERK signaling, as specific inhibitors of these pathways reduce IRES-mediated translation and protein levels under conditions of quiescent AKT activity. Thus, continued IRES-mediated translation initiation may permit cell cycle progression upon mTOR inactivation in cells in which AKT kinase activity is relatively low.