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News Article | November 21, 2016
Site: www.eurekalert.org

A cellular component known as the Golgi apparatus may play a role in how lung cancer metastasizes, according to researchers at The University of Texas MD Anderson Cancer Center whose findings were reported in the Nov. 21 online issue of the Journal of Clinical Investigation. The Golgi apparatus, often referred to as a cellular "post office" for its ability to package proteins into vesicles for transportation to other sites within or outside the cell, may offer a new therapeutic approach for preventing metastasis. Think of vesicles as miniature mail trucks composed of a fatty shell filled with secretory liquids that travel from the Golgi to destinations within the cell where their contents are put to use. The Golgi can appear as a compacted membranous "stack" near the cell's nucleus or as a dispersed system of interconnected membranes. Vesicles can "bud" from the Golgi in either form. "Our findings show that certain proteins in the Golgi that control Golgi compaction may actually promote vesicle budding and transport and enhance the tumor cell's ability to metastasize" said Jonathan Kurie, M.D., professor of Thoracic Head and Neck Medical Oncology. "These findings highlight the potential utility of targeting certain cellular processes in the Golgi." According to Kurie, tumor cells gain their metastatic ability through a Golgi-related process driving the budding and transport of secretory vesicles. Unknown before this study was whether Golgi compaction was responsible for vesicular trafficking leading to metastasis. This study shows that Golgi compaction is associated with EMT or epithelial-to-mesenchymal transition, a process that allows a cell to detach and move away from its neighbors during wound healing and other normal processes and is thought to play a role in cancer cell migration. Using lung adenocarcinoma cell lines isolated from mice and patients, Kurie's team found that EMT depends on a Golgi protein called PAQR11 for successful tumor cell migration and metastasis in lung cancers. "We concluded that, through PAQR11, tumor cells can hijack a normal Golgi compaction process in order to gain metastatic ability," said Kurie. MD Anderson study team participants included Xiaochao Tan, Ph.D.; Priyam Banerjee; Ph.D., Hou-Fu Guo, Ph.D.; Daniela Pankova, Ph.D.; Xin Liu, Ph.D.;Yongming Xue, Jonathon Roybal and Don Gibbons, M.D., all of Thoracic Head and Neck Medical Oncology; Tomasz Zal, Ph.D., Immunology; and Chad Creighton, Ph.D., Bioinformatics and Computational Biology. Other participating institutions include the University of Michigan, Ann Arbor, Mich.; Ewha Woman's University School of Medicine, Seoul, South Korea; University of York, York, U.K.; Harbin Medical University Cancer Hospital, Harbin, China; University of Houston and Baylor College of Medicine, Houston. The study was funded by the National Institutes of Health (R01CA181184, R01CA125123, GM087364, GM105920, GM112786P30, EY007551, K08CA151661, NRF-2010-0027945, CA015672, 1S10OD012304-01, and 1S10RR09552-01), the American Cancer Society (RGS-09-278-01-CSM), the Cancer Prevention Research Institute of Texas (RP120713), and MCubed and the Fastforward Protein Folding Disease Initiative at the University of Michigan.


News Article | March 1, 2017
Site: www.eurekalert.org

HOUSTON ? Anyone who uses an employee badge to enter a building may understand how a protein called ENL opens new possibilities for treating acute myeloid leukemia (AML), a fast-growing cancer of bone marrow and blood cells and the second most common type of leukemia in children and adults. Findings from a study at The University of Texas MD Anderson Cancer Center revealed the leukemia-boosting abilities of ENL, which contains a protein component called YEATS that "reads" histone proteins. Histone proteins make up chromatin, large clusters of DNA- and RNA-containing molecules comprising our body's chromosomes. Just as a scanner "reads" data on an identification badge, ENL recognizes a type of histone modification known as acetylation. Research results, which build upon a previous MD Anderson study of histone-reading proteins, are published in the March 1 online issue of Nature. The findings indicated treatment against ENL with a class of experimental drugs called bromodomain and extra-terminal (BET) inhibitors may be effective for treating AML. "Our study showed that ENL is required for disease maintenance in AML," said Xiaobing Shi, Ph.D., associate professor of Epigenetics and Molecular Carcinogenesis. "Depletion of ENL led to anti-leukemic effects, suppressing growth both in vivo and in vitro. Notably, disrupting ENL further sensitized leukemia cells to BET inhibitors." Histone modifications like acetylation serve as docking sites for reader proteins which recognize specific modifications, influencing downstream biological outcomes. While many such reader proteins have been identified for histone modifications called methylation, few are known to recognize histone acetylation. Shi's team employed CRISPR, a gene-editing tool, to deplete ENL and suppress cancer gene expression, which was crucial given that cancer cells often co-opt chromatin regulatory pathways. "Targeting epigenetic readers represents a class of anti-cancer therapy that we believe holds clinical promise," said Hong Wen, Ph.D., research assistant professor of Epigenetics and Molecular Carcinogenesis and co-first author of the paper. "Our study revealed ENL as a chromatin reader that regulates oncogenic programs, thus establishing ENL as a potential drug target for AML." MD Anderson study team members included Xiaolu Wang of the Department of Epigenetics and Molecular Carcinogenesis. Other participating institutions included The Rockefeller University, New York; Memorial Sloan Kettering Cancer Center, New York; Dana-Farber Cancer Institute, Boston; Tsinghua University, Beijing; Baylor College of Medicine, Houston; Icahn School of Medicine at Mount Sinai, New York; and Harvard Medical School; Boston. The study was funded by the National Institutes of Health (P30CA016672, RO1CA204639-01, CA66996, CA140575, 1R01CA204020, R01HG007538 and R01CA193466), the Cancer Prevention Research Institute of Texas (RP160237 and RP170285), the Leukemia and Lymphoma Society (LLS-SCOR 7006-13), the Robert A. Welch Foundation (G1719), the Major State Basic Research Development Program in China (2016FA0500700 and 2015CB910503), and the Tsinghua University Initiative Research program.


Rosengren D.B.,Prevention Research Institute | Rosengren D.B.,University of Washington | Beadnell B.,Prevention Research Institute | Beadnell B.,University of Washington | And 3 more authors.
Substance Abuse: Treatment, Prevention, and Policy | Year: 2012

Background: There is significant interest in the value of motivational approaches that enhance participant readiness to change, but less is known about clients' self-reports of problematic behavior when participating in such interventions.Methods: We examined whether participants in a motivationally-based intervention for DUI offenders changed their reports of substance use at postintervention (when reporting on the same 30 days that they reported on at preintervention). Specifically, Study 1 (N = 8,387) tested whether participants in PRIME For Life (PFL) changed their reports about baseline substance levels when asked at postintervention versus at preintervention. Study 2 (N = 192) compared changes in self-reported baseline drinking between PFL and intervention as usual (IAU) participants.Results: Many participants in Study 1 did not change their reports about how much they used substances during the 30-day period before baseline. Among those who did, the most common change was an increase in reported amounts of baseline drug use, and typical and peak alcohol use. This sample also showed changes in reports of their baseline pattern of high-risk-use (consistent versus occasional). At postintervention, participants who were younger, single, or endorsing more indicators of alcohol dependence were more likely to later report greater frequency of baseline drug use, and greater peak and typical number of baseline drinks. Gender, education, and race were also associated with reporting inconsistency on some behaviors. In Study 2, PFL participants showed greater increases in reports of peak alcohol use compared to IAU, but both conditions showed similar increases for drugs and typical alcohol use.Conclusions: In both research and clinical settings, a segment of participants may initially report less substance use than they do when asked later about the same baseline period. These preliminary findings suggest clinicians and researchers may find postintervention evaluations yield reports of greater baseline alcohol or drug use for some people. For some behaviors, this may occur more often in interventions that target client motivation. Future research should attempt to identify which reports - preintervention vs. postintervention - better reflect actual baseline substance use. © 2012 Rosengren et al.; licensee BioMed Central Ltd.


Imel Z.E.,University of Utah | Baldwin S.A.,Brigham Young University | Baer J.S.,University of Washington | Hartzler B.,University of Washington | And 3 more authors.
Journal of Consulting and Clinical Psychology | Year: 2014

Objective: The goal of measuring therapist adherence is to determine whether a therapist can perform a given treatment. Yet, the evaluation of therapist behaviors in most clinical trials is limited. Typically, randomized trials have few therapists and minimize therapist variability through training and supervision. Furthermore, therapist adherence is confounded with uncontrolled differences in patients across therapists. Consequently, the extent to which adherence measures capture differences in actual therapist adherence versus other sources of variance is unclear. Method: We estimated intra-class correlations (ICCs) for therapist adherence in sessions with real and standardized patients (RPs and SPs), using ratings from a motivational interviewing (MI) dissemination trial (Baer et al., 2009) in which 189 therapists recorded 826 sessions with both patient types. We also examined the correlations of therapist adherence between SP and RP sessions, and the reliability of therapist level adherence scores with generalizability coefficients (GCs). Results: ICCs for therapist adherence were generally large (average ICC for SPs =.44; average ICC for RPs =.40), meaning that a given therapist's adherence scores were quite similar across sessions. Both ICCs and GCs were larger for SP sessions compared to RPs on global measures of MI adherence, such as Empathy and MI Spirit. Correlations between therapist adherence with real and standardized patients were moderate to large on 3 of 5 adherence measures. Conclusion: Differences in therapist-level adherence ratings were substantial, and standardized patients have promise as tools to evaluate therapist behavior. © 2014 American Psychological Association.


Beadnell B.,Prevention Research Institute | Beadnell B.,University of Washington | Nason M.,Prevention Research Institute | Stafford P.A.,Prevention Research Institute | And 3 more authors.
Accident Analysis and Prevention | Year: 2012

Objective: We compared a group-delivered, theory-based, motivation-enhancing program (PRIME For Life ® - PFL, n = 450) to an intervention as usual (IAU, n = 72). Method: Individuals convicted of a substance related offense in North Carolina, typically first offense alcohol and drug-impaired driving, participated in a PFL or IAU group. We compare the interventions on program satisfaction and changes made from preintervention to postintervention, and examined the moderating effects of demographics and alcohol dependence level. Results: When significant, findings varied in magnitude from small to medium effects. Participants in both interventions showed intentions to use statistically significantly less alcohol and drugs in the future compared to their previous use, and differences between the groups were not statistically significant. Otherwise, findings favored PFL. PFL exhibited greater benefit than IAU on understanding tolerance, perceived risk for addiction, problem recognition, and program satisfaction. Additionally, IAU perceived less risk for negative consequences postintervention than they had at preintervention. Moderation analyses showed that the between-condition findings occurred regardless of gender, age, education, and number of alcohol dependence indicators. Additionally, younger people and those with more dependence indicators - groups of particular concern - showed the greatest change. Conclusions: Findings suggest that a motivation-enhancing approach can be effective in producing short-term change in factors that can help facilitate and sustain behavioral change. This is consistent with previous research on the use of motivational approaches, and extends such findings to suggest promise in group-based settings and with people across demographic categories and dependence levels. Future research should focus on larger studies looking at long-term behavioral change, including recidivism. © 2011 Elsevier Ltd. All rights reserved.


Baer J.S.,University of Washington | Carpenter K.M.,Talaria, Inc. | Beadnell B.,University of Washington | Beadnell B.,Prevention Research Institute | And 6 more authors.
Journal of Studies on Alcohol and Drugs | Year: 2012

Objective: Benefits of empirically supported interventions hinge on clinician skill, particularly for motivational interviewing (MI). Existing MI skill assessments are limited with respect to validity (e.g., self-report) and practicality (e.g., coding session tapes). To address these limitations, we developed and evaluated two versions of a webbased assessment of MI skills, the Computer Assessment of Simulated Patient Interviews (CASPI). Method: Ninety-six counselors from the community and 24 members of the Motivational Interviewing Network of Trainers (MINT) completed the CASPI (N = 120), in which they verbally responded via microphones to video clips comprising three 9-item vignettes. Three coders used an emergent coding scheme, which was compared with alternative MI skills measures. Results: CASPI demonstrated excellent internal consistency when averaging across two or three vignettes (α's =.86-.89). Intraclass correlations were above.40 for most items. Confi rmatory factor analyses supported a correlated three-factor model: MI-consistent, resistance-engendering, and global change talk orientation rating. Means and factor loadings were invariant across forms (i.e., the two alternative versions of CASPI), and factor loadings were invariant across subgroup (i.e., community counselor or MINT member). Test-retest reliability was good for MI-consistent and resistance-engendering scores (r =.74 and.80, respectively) but low for change talk orientation (r =.29) unless coder was taken into account (r =.69). CASPI showed excellent construct and criterion-related validity. Conclusions: CASPI represents a promising method of assessing MI skills. Future studies are needed to establish its performance in realworld contexts.


PubMed | University of Washington, Prevention Research Institute and University of Maryland Baltimore County
Type: Journal Article | Journal: Evaluation & the health professions | Year: 2016

Assessing the practical or clinical significance (CS) of an intervention programs outcomes is useful in determining its effectiveness. The CS approach gives information beyond traditional analyses by quantifying the proportions of people who meaningfully improve and deteriorate. We link latent transition analyses (LTA) to the CS literature and use a case study to contrast it with the long-standing Jacobson and Truax (JT) approach. Data came from 2,717 individuals convicted of a substance-related offense who participated in an indicated prevention program Prime For Life


PubMed | University of Washington, Prevention Research Institute and University of Maryland Baltimore County
Type: Journal Article | Journal: Addiction science & clinical practice | Year: 2016

Emerging adulthood is an age of particularly risky behavior. Substance misuse during this phase of life can be the beginning of longer-term problems, making intervention programs particularly important. This studys purposes were to identify alcohol use profile subgroups, describe the preintervention characteristics of each, and assess how many participants transitioned to lower-risk profiles during the course of the intervention.We used latent transition analyses to categorize 1183 people court ordered to attend Prime For LifeProfiles included two low-risk statuses (abstinence and light drinking) and two high-risk statuses (occasional heavy drinking and frequent heavy drinking). We found that people in profile subgroups that reflected heavier 90-day preintervention drinking were likely to transition to profiles reflecting postintervention intentions for lower-risk drinking in the subsequent 90days. In contrast, the likelihood of transitioning from a lower-risk to a higher-risk profile was extremely low. These positive changes were found for people of both sexes and for those above versus below the legal drinking age, albeit for more women than men in the heaviest drinking group.Findings showed positive changes during intervention for many emerging adult participants attending PFL. Further research is needed that include comparison conditions, as well as examine longer-term outcomes in this population.


PubMed | Prevention Research Institute and University of Maryland Baltimore County
Type: | Journal: Accident; analysis and prevention | Year: 2015

Operating a motor vehicle under the influence of alcohol (OUI) is an international problem. In the United States, one intervention strategy is to require offenders to attend group-delivered interventions. We compared three year rearrest rates among 12,267 individuals in Maine receiving either a motivation-enhancing (ME) program, Prime For Life(), or historical standard care (SC) programs. We created two cohorts, one when Maine used SC (9/1/1999-8/31/2000) and one after the ME program was implemented (9/1/2002-8/31/2003). Adjusted for control variables, rearrest rates among people not completing an assigned program did not differ for the ME versus SC cohorts (12.1% and 11.6%, respectively; OR=1.05, ns). In contrast, ME compared to SC program completers had lower rearrest rates (7.4% versus 9.9%, OR=0.73, p<.05). The same pattern occurred for people required to take these programs plus substance use treatment (12.1% versus 14.7%, OR=0.82, p<.01). For those rearrested, time to rearrest did not differ between ME and SC cohorts. Among those required to have substance abuse treatment, ME and SC arrest rates did not differ for younger individuals; otherwise, the ME cohorts lower rearrest rates occurred across gender, age, having a previous OUI, and having completed a previous intervention program.


PubMed | Prevention Research Institute
Type: | Journal: Substance abuse treatment, prevention, and policy | Year: 2013

There is significant interest in the value of motivational approaches that enhance participant readiness to change, but less is known about clients self-reports of problematic behavior when participating in such interventions.We examined whether participants in a motivationally-based intervention for DUI offenders changed their reports of substance use at postintervention (when reporting on the same 30 days that they reported on at preintervention). Specifically, Study 1 (N = 8,387) tested whether participants in PRIME For Life (PFL) changed their reports about baseline substance levels when asked at postintervention versus at preintervention. Study 2 (N = 192) compared changes in self-reported baseline drinking between PFL and intervention as usual (IAU) participants.Many participants in Study 1 did not change their reports about how much they used substances during the 30-day period before baseline. Among those who did, the most common change was an increase in reported amounts of baseline drug use, and typical and peak alcohol use. This sample also showed changes in reports of their baseline pattern of high-risk-use (consistent versus occasional). At postintervention, participants who were younger, single, or endorsing more indicators of alcohol dependence were more likely to later report greater frequency of baseline drug use, and greater peak and typical number of baseline drinks. Gender, education, and race were also associated with reporting inconsistency on some behaviors. In Study 2, PFL participants showed greater increases in reports of peak alcohol use compared to IAU, but both conditions showed similar increases for drugs and typical alcohol use.In both research and clinical settings, a segment of participants may initially report less substance use than they do when asked later about the same baseline period. These preliminary findings suggest clinicians and researchers may find postintervention evaluations yield reports of greater baseline alcohol or drug use for some people. For some behaviors, this may occur more often in interventions that target client motivation. Future research should attempt to identify which reports - preintervention vs. postintervention - better reflect actual baseline substance use.

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