Resistance to PRMT5-targeted therapy in mantle cell lymphoma.

ABSTRACT: Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma, and patients who relapse on targeted therapies have poor prognosis. Protein arginine methyltransferase 5 (PRMT5), an enzyme essential for B-cell transformation, drives multiple oncogenic pathways and is overexpressed in MCL. Despite the antitumor activity of PRMT5 inhibition (PRT-382/PRT-808), drug resistance was observed in a patient-derived xenograft (PDX) MCL model. Decreased survival of mice engrafted with these PRMT5 inhibitor-resistant cells vs treatment-naive cells was observed (P = .005). MCL cell lines showed variable sensitivity to PRMT5 inhibition. Using PRT-382, cell lines were classified as sensitive (n = 4; 50% inhibitory concentration [IC50], 20-140 nM) or primary resistant (n = 4; 340-1650 nM). Prolonged culture of sensitive MCL lines with drug escalation produced PRMT5 inhibitor-resistant cell lines (n = 4; 200-500 nM). This resistant phenotype persisted after prolonged culture in the absence of drug and was observed with PRT-808. In the resistant PDX and cell line models, symmetric dimethylarginine reduction was achieved at the original PRMT5 inhibitor IC50, suggesting activation of alternative resistance pathways. Bulk RNA sequencing of resistant cell lines and PDX relative to sensitive or short-term-treated cells, respectively, highlighted shared upregulation of multiple pathways including mechanistic target of rapamycin kinase [mTOR] signaling (P < 10-5 and z score > 0.3 or < 0.3). Single-cell RNA sequencing analysis demonstrated a strong shift in global gene expression, with upregulation of mTOR signaling in resistant PDX MCL samples. Targeted blockade of mTORC1 with temsirolimus overcame the PRMT5 inhibitor-resistant phenotype, displayed therapeutic synergy in resistant MCL cell lines, and improved survival of a resistant PDX.

Mindfulness-based school interventions: A systematic review of outcome evidence quality by study design.

Objective: The purpose of this systematic review was to assess the current literature on mindfulness-based school interventions (MBSIs) by evaluating evidence across specific outcomes for youth. Methods: We evaluated 77 studies with a total sample of 12,358 students across five continents, assessing the quality of each study through a robust coding system for evidence-based guidelines. Coders rated each study numerically per study design as 1++ (RCT with a very low risk of bias) to 4 (expert opinion) and across studies for the corresponding evidence letter grade, from highest quality ('A Grade') to lowest quality ('D Grade') evidence. Results: The highest quality evidence ('A Grade') across outcomes indicated that MBSIs increased prosocial behavior, resilience, executive function, attention and mindfulness, and decreased anxiety, attention problems/ADHD behaviors and conduct behaviors. The highest quality evidence for well-being was split, with some studies showing increased well-being and some showing no improvements. The highest quality evidence suggests MBSIs have a null effect on depression symptoms. Conclusion: This review demonstrates the promise of incorporating mindfulness interventions in school settings for improving certain youth outcomes. We urge researchers interested in MBSIs to study their effectiveness using more rigorous designs (e.g., RCTs with active control groups, multi-method outcome assessment, and follow-up evaluation), to minimize bias and promote higher quality-not just increased quantity-evidence that can be relied upon to guide school-based practice.

Integrative Reiki for cancer patients: a program evaluation.

OBJECTIVE: This mixed methods study sought to evaluate the outcomes of an integrative Reiki volunteer program in an academic medical oncology center setting. METHOD: We used de-identified program evaluation data to perform both quantitative and qualitative analyses of participants' experiences of Reiki sessions. The quantitative data were collected pre- and postsession using a modified version of the distress thermometer. The pre- and postsession data from the distress assessment were analyzed using a paired Student's : test. The qualitative data were derived from written responses to open-ended questions asked after each Reiki session and were analyzed for key words and recurring themes. RESULTS: Of the 213 pre-post surveys of first-time sessions in the evaluation period, we observed a more than 50% decrease in self-reported distress (from 3.80 to 1.55), anxiety (from 4.05 to 1.44), depression (from 2.54 to 1.10), pain (from 2.58 to 1.21), and fatigue (from 4.80 to 2.30) with P < .001 for all. Using conservative estimates that treat missing data as not endorsing Reiki, we found 176 (82.6%) of participants liked the Reiki session, 176 (82.6%) found the Reiki session helpful, 157 (73.7%) plan to continue using Reiki, and 175 (82.2%) would recommend Reiki to others. Qualitative analyses found that individuals reported that Reiki induced relaxation and enhanced spiritual well-being. CONCLUSIONS: An integrative Reiki volunteer program shows promise as a component of supportive care for cancer patients. More research is needed to evaluate and understand the impact that Reiki may have for patients, caregivers, and staff whose lives have been affected by cancer.

Breast cancer survivors willingness to participate in an acupuncture clinical trial: a qualitative study.

PURPOSE: Acupuncture is a complementary and alternative medicine (CAM) modality that shows promise as a component of supportive breast cancer care. Lack of robust recruitment for clinical trial entry has limited the evidence base for acupuncture as a treatment modality among breast cancer survivors. The objective of this study is to identify key decision-making factors among breast cancer survivors considering entry into an acupuncture clinical trial for treatment of symptoms. METHODS: Semistructured interviews were conducted among African-American (n=12) and Caucasian (n=13) breast cancer survivors. Verbatim transcripts were made and analyzed by two or more independent coders using NVivo software. Major recurring themes were identified and a theoretical framework developed. RESULTS: Six themes emerged reflecting key attributes of the decision to enter a clinical trial: (1) symptom appraisal, (2) practical barriers (e.g., distance and travel), (3) beliefs about the interventions (e.g., fear of needles and dislike of medications), (4) comfort with elements of clinical trial design (e.g., randomization, the nature of the control intervention, and blinding), (5) trust, and (6) altruism. African-American and Caucasian women weighed similar attributes but differed in the information sources sought regarding clinical trial entry and in concerns regarding the use of a placebo in a clinical trial. CONCLUSIONS: Our findings contribute to the development of a theoretical model of decision making for breast cancer survivors considering participation in a CAM clinical trial. Insights regarding the decision making process can inform interventions to support informed decision making and robust recruitment to CAM trials among cancer survivors.

He thought the "lady in the door" was the "lady in the window": a qualitative study of patient identification practices.

BACKGROUND: Accurate patient identification (PT ID) is a key component in hospital patient safety practices and was addressed by one of the first six Joint Commission National Patient Safety Goals, which were introduced in 2003. Although the literature on patient safety practices is replete with discussion of strategies for improvement, less is known about frontline providers' subjective views. A qualitative study was conducted to examine the subjective views and experiences of nurses and residents regarding PT ID at an urban teaching hospital. METHODS: Some 15 registered nurses and 15 residents were interviewed between August 2009 and June 2010. Transcripts were analyzed using qualitative methodologies. FINDINGS: Although residents and nurses viewed PT ID as crucial to patient safety, they cited time pressures; confidence in their ability to informally identify patients; and a desire to deliver personal, humanistic care as reasons for not consistently verifying patient identification. Nurses expressed concern about annoying, offending, and/or alienating patients by repeatedly checking wristbands and asking date of birth, in the belief that excessive patient identification practices could undermine trust. Residents relied on nurses to check ID and preferred to greet the patient by name, a practice that they viewed as more consistent with their professional identity. Referring to patients by their room number and location was cited as a commonly used practice of PT ID and a contributor to errors in identification. CONCLUSIONS: Nurses and residents are aware of the importance and requirements to verify PT ID, but their adherence is mitigated by a variety of factors, including assessment of necessity or risk, impact on their relationship with the patient, and practices in place in the hospital environment that protect patient privacy.

Effective and viable mind-body stress reduction in the workplace: a randomized controlled trial.

Highly stressed employees are subject to greater health risks, increased cost, and productivity losses than those with normal stress levels. To address this issue in an evidence-based manner, worksite stress management programs must be able to engage individuals as well as capture data on stress, health indices, work productivity, and health care costs. In this randomized controlled pilot, our primary objective was to evaluate the viability and proof of concept for two mind-body workplace stress reduction programs (one therapeutic yoga-based and the other mindfulness-based), in order to set the stage for larger cost-effectiveness trials. A second objective was to evaluate 2 delivery venues of the mindfulness-based intervention (online vs. in-person). Intention-to-treat principles and 2 (pre and post) × 3 (group) repeated-measures analysis of covariance procedures examined group differences over time on perceived stress and secondary measures to clarify which variables to include in future studies: sleep quality, mood, pain levels, work productivity, mindfulness, blood pressure, breathing rate, and heart rate variability (a measure of autonomic balance). Two hundred and thirty-nine employee volunteers were randomized into a therapeutic yoga worksite stress reduction program, 1 of 2 mindfulness-based programs, or a control group that participated only in assessment. Compared with the control group, the mind-body interventions showed significantly greater improvements on perceived stress, sleep quality, and the heart rhythm coherence ratio of heart rate variability. The two delivery venues for the mindfulness program produced basically equivalent results. Both the mindfulness-based and therapeutic yoga programs may provide viable and effective interventions to target high stress levels, sleep quality, and autonomic balance in employees.

Observed parenting behavior with teens: measurement invariance and predictive validity across race.

Previous reports supporting measurement equality between European American and African American families have often focused on self-reported risk factors or observed parent behavior with young children. This study examines equality of measurement of observer ratings of parenting behavior with adolescents during structured tasks; mean levels of observed parenting; and predictive validity of teen self-reports of antisocial behaviors and beliefs using a sample of 163 African American and 168 European American families. Multiple-group confirmatory factor analyses supported measurement invariance across ethnic groups for four measures of observed parenting behavior: prosocial rewards, psychological costs, antisocial rewards, and problem solving. Some mean-level differences were found: African American parents exhibited lower levels of prosocial rewards, higher levels of psychological costs, and lower problem solving when compared to European Americans. No significant mean difference was found in rewards for antisocial behavior. Multigroup structural equation models suggested comparable relationships across race (predictive validity) between parenting constructs and youth antisocial constructs (i.e., drug initiation, positive drug attitudes, antisocial attitudes, problem behaviors) in all but one of the tested relationships. This study adds to existing evidence that family-based interventions targeting parenting behaviors can be generalized to African American families.

Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress.

Tight regulation of intracellular iron levels in response to mitochondrial dysfunction is an important mechanism that prevents oxidative stress, thereby limiting cellular damage. Here, we describe a cytoprotective response involving transcriptional activation of the ferritin H gene in response to the mitochondrial complex I inhibitor and neurotoxic compound rotenone. Rotenone exposure increased ferritin H mRNA and protein synthesis in NIH3T3 fibroblasts and SH-SY5Y neuroblastoma cells. Transient transfection of a ferritin H promoter-luciferase reporter into NIH3T3 cells showed that ferritin H was transcriptionally activated by rotenone through an antioxidant-responsive element (ARE). Chromatin immunoprecipitation assays showed that rotenone treatment enhanced binding of Nrf2 and JunD transcription factors to the ARE. In addition, rotenone induced production of reactive oxygen species (ROS), and pretreatment with N-acetylcysteine abrogated ferritin H mRNA induction by rotenone, suggesting that this response is oxidative stress-mediated. Furthermore, reduced ferritin H expression by siRNA sensitized cells to rotenone-induced apoptosis with increased ROS production and annexin V-positive cells. Taken together, these results suggest that ferritin H transcription is activated by rotenone via an oxidative stress-mediated pathway leading to ARE activation and may be critically important to protect cells from mitochondrial dysfunction and oxidative stress.

Intracellular iron transport and storage: from molecular mechanisms to health implications.

Maintenance of proper "labile iron" levels is a critical component in preserving homeostasis. Iron is a vital element that is a constituent of a number of important macromolecules, including those involved in energy production, respiration, DNA synthesis, and metabolism; however, excess "labile iron" is potentially detrimental to the cell or organism or both because of its propensity to participate in oxidation-reduction reactions that generate harmful free radicals. Because of this dual nature, elaborate systems tightly control the concentration of available iron. Perturbation of normal physiologic iron concentrations may be both a cause and a consequence of cellular damage and disease states. This review highlights the molecular mechanisms responsible for regulation of iron absorption, transport, and storage through the roles of key regulatory proteins, including ferroportin, hepcidin, ferritin, and frataxin. In addition, we present an overview of the relation between iron regulation and oxidative stress and we discuss the role of functional iron overload in the pathogenesis of hemochromatosis, neurodegeneration, and inflammation.

Elevated intracellular calcium increases ferritin H expression through an NFAT-independent post-transcriptional mechanism involving mRNA stabilization.

An increase in intracellular Ca2+ is one of the initiating events in T-cell activation. A calcium-mediated signalling cascade in T-cells involves activation of calcineurin and the dephosphorylation and translocation of NFAT (nuclear factor of activated T-cells), resulting in the transcriptional activation of target genes such as IL-2 (interleukin-2). In the present study, we found that increased intracellular calcium leads to induction of the antioxidant protein ferritin H. We previously reported that the ferritin H gene is transcriptionally activated under oxidative stress conditions through an ARE (antioxidant-responsive element). The facts that the ferritin H ARE contains a composite AP-1 (activator protein 1) site and that NFAT collaborates with AP-1 transcription factors led us to test whether calcium-activated NFAT is involved in the ferritin H induction through the ARE. Treatment of Jurkat T-cells with the calcium ionophore, ionomycin, increased ferritin H mRNA and protein expression. Although NFAT translocated to the nucleus and bound a consensus NFAT sequence located in the IL-2 promoter after ionomycin treatment, it did not activate ferritin H transcription despite the presence of a putative NFAT-binding sequence in the ferritin H ARE. In addition, the calcineurin inhibitor cyclosporin A treatment blocked ionomycin-mediated NFAT nuclear translocation but failed to abrogate the increase in ferritin H mRNA. Analysis of mRNA stability after actinomycin D treatment revealed that ionomycin prolongs ferritin H mRNA half-life. Taken together, these results suggest that ionomycin-mediated induction of ferritin H may occur in an NFAT-independent manner but through post-transcriptional stabilization of the ferritin H mRNA.

Regaining our humanity through story.

In this issue of Innovations in Integrative Healthcare Education, we are departing from our usual format of spotlighting specific projects or programs in lieu of presenting a more extended piece by MacKenzie on relationship-centered care and narrative medicine. The importance of these topics cannot be overestimated in their role of humanizing the healthcare encounter, improving self-awareness of the practitioner, and creating a space in which the patient feels deeply listened to. A commentary by Dr Michelle Sierpina is also included in this special section to put into context the power of narrative in medicine and in patients' lives. Her recent PhD focused on the power of life stories told by seniors; that research and training enables her to provide a broad and scholarly review of the power of story in relation to MacKenzie's article. In the medical school at University of Texas Medical Branch, we send out first-year medical students in the first couple of months of the first semester to patients' homes to just get their story, not a medical history, as part of a required course on the practice of medicine. Many students find this immensely anxiety provoking, due to the lack of structure and familiar context. However, ultimately they find an opportunity to encounter a real person in a nonclinical setting. A scoring rubric based on the construction and quality of a short story allows us to grade the students objectively. However, a most interesting finding, which we expect to present at the Ottawa Conference in Australia next spring, is the process of personal transformation that such story writing has for students. This is also reported by MacKenzie in her article and in Sierpina's accompanying commentary. The importance of capturing and understanding the patient's story is also a major focus in nurse practitioner programs across the United States, where the art of listening and the importance of patient narratives have long been emphasized. In an integrative assessment of patients, we "make a history" rather than "take a history." This means that we coconstruct with the patient the reality of the medical encounter and the tone and timbre of the healing relationship. By bringing our own culture, beliefs, and values to the exam room and then allowing the patient to share theirs with us, we create a new kind of relationship-centered, patient-centered care model. This allows the strength of the linear standard medical history, chief complaint, history of present illness, past history, social/family history, review of systems, etc, to be informed and enriched by the nonlinear, perhaps circular, patient story. This story making further allows deeper exploration of the patient's life goals as well as their medical goals.(1) It creates increased personalization of the provider-patient relationship and moves from the "I-them" to Buber's "I-thou." Enjoy the article and the accompanying commentary and consider how to implement this kind of care and mindfulness into the education of health professional students and your practice.

A randomized trial of Parents Who Care: effects on key outcomes at 24-month follow-up.

This study was designed to test the efficacy of Parents Who Care (PWC), a seven-session universal prevention program which includes parenting, youth, and family components designed to prevent substance use and other problem behaviors. Using an intent-to-treat experimental design, this study tests the program efficacy across race within a balanced sample of European American (EA) and African American (AA) youth and their parents (n = 331 n AA = 163; n EA = 168). Families were recruited, randomly assigned to three conditions (group-administered [PA], self-administered with telephone support [SA], and no-treatment control) and the intervention was administered when the adolescents were in the eighth grade. Analyses on key teen outcomes of the Parent's Who Care program at 24-month follow-up are reported here and include perceptions of drug use harm; favorable attitudes about drug use; delinquent and violent behavior; and initiation into cigarette, alcohol, other drug use, or sexual activity. Repeated measures mixed model regressions found no effect of the intervention on rate of change in attitudes about drug use or frequency of delinquent or violent behavior. Regression analyses with multiple imputations for missing data detected group differences in means at 24-month follow-up. Both program formats reduced favorable attitudes toward drug use among youth (SA d = 0.39, PA d = 0.22); and AA youth in the self-administered intervention reported significantly less violent behavior than their control counterparts (d = 0.45). No effects were found for drug use harm or delinquency. Finally, logistic regression predicting a combined outcome measure of initiation of alcohol, tobacco, drug use, and/or sexual activity found AA youth in both the group- and self-administered intervention conditions significantly less likely to initiate substance use and/or sexual activity than those in the control condition. Odds ratios indicated the chances of initiating sex or substance use were reduced by almost 70% (OR = 0.31) for AA teens in the SA condition compared to controls, and 75% (OR = 0.25) for the AA teens in the PA compared to controls.

Is real reform of the Medicare Benefits Schedule for psychiatrists in Australia economically, socially or professionally desirable?

OBJECTIVE: To propose alternative Medicare Benefits Schedule-based funding models for outpatient psychiatric services in Australia. METHOD: Development of alternative funding schedules for a variety of under-serviced populations. CONCLUSIONS: Consideration of alternative systems is necessary to address the restrictive work practices, inequity and poor distribution of the psychiatric workforce.

Hemin-mediated regulation of an antioxidant-responsive element of the human ferritin H gene and role of Ref-1 during erythroid differentiation of K562 cells.

An effective utilization of intracellular iron is a prerequisite for erythroid differentiation and hemoglobinization. Ferritin, consisting of 24 subunits of H and L, plays a crucial role in iron homeostasis. Here, we have found that the H subunit of the ferritin gene is activated at the transcriptional level during hemin-induced differentiation of K562 human erythroleukemic cells. Transfection of various 5' regions of the human ferritin H gene fused to a luciferase reporter into K562 cells demonstrated that hemin activates ferritin H transcription through an antioxidant-responsive element (ARE) that is responsible for induction of a battery of phase II detoxification genes by oxidative stress. Gel retardation and chromatin immunoprecipitation assays demonstrated that hemin induced binding of cJun, JunD, FosB, and Nrf2 b-zip transcription factors to AP1 motifs of the ferritin H ARE, despite no significant change in expression levels or nuclear localization of these transcription factors. A Gal4-luciferase reporter assay did not show activation of these b-zip transcription factors after hemin treatment; however, redox factor 1 (Ref-1), which increases DNA binding of Jun/Fos family members via reduction of a conserved cysteine in their DNA binding domains, showed induced nuclear translocation after hemin treatment in K562 cells. Consistently, Ref-1 enhanced Nrf2 binding to the ARE and ferritin H transcription. Hemin also activated ARE sequences of other phase II genes, such as GSTpi and NQO1. Collectively, these results suggest that hemin activates the transcription of the ferritin H gene during K562 erythroid differentiation by Ref-1-mediated activation of these b-zip transcription factors to the ARE.

Participation in "parents who care": predicting program initiation and exposure in two different program formats.

Predictors of participation and exposure across two formats of a universal prevention program are examined here. Families of 225 8th-grade students, balanced by race (African American and European American) and gender, were assigned to a parent and adolescent group format (PAG) or a self-administered format (SA). Logistic regression showed greater program initiation in SA than in PAG. Hierarchical regression showed only one variable (parent high-risk behavior) to be associated with lower program exposure in the self-administered format. In contrast, demographic variables (e.g., being African American) predicted lower exposure in PAG. Overall, the findings of this study were notable in that most of the variables that have been identified in past research as lowering participation rates were not related to program initiation or level of exposure to either format of Parents Who Care. Further, the self-administered format may be particularly useful to increase program participation for families, even those who are traditionally difficult to reach. Editors' Strategic Implications: The authors make a promising contribution to the literature on program engagement by presenting experimental data highlighting different risk factors for nonparticipation across program formats. Their discussion of barriers will help program designers and practitioners decide on the most appropriate strategies for the dissemination of prevention-related materials to parents.

Reducing playground bullying and supporting beliefs: an experimental trial of the steps to respect program.

Six schools were randomly assigned to a multilevel bullying intervention or a control condition. Children in Grades 3-6 (N=1,023) completed pre- and posttest surveys of behaviors and beliefs and were rated by teachers. Observers coded playground behavior of a random subsample (n=544). Hierarchical analyses of changes in playground behavior revealed declines in bullying and argumentative behavior among intervention-group children relative to control-group children, increases in agreeable interactions, and a trend toward reduced destructive bystander behavior. Those in the intervention group reported enhanced bystander responsibility, greater perceived adult responsiveness, and less acceptance of bullying/aggression than those in the control group. Self-reported aggression did not differ between the groups. Implications for future research on the development and prevention of bullying are discussed.

Use of CAM in local African-American communities: community-partnered research.

Although previous national surveys have shown an increase in the use of complementary and alternative medicine (CAM) in the U.S. population, racial and ethnic minority populations were under-represented in these surveys. As a result, a profile of the CAM user as white, female, affluent, middle-aged and well educated has emerged. Representing the mainstream population, these previous studies did not take into account the racial and ethnic minority populations who may have their own healing traditions and who may hold different beliefs, use different terminology, and have unique patterns of CAM use. In partnership with community-based organizations and community residents, a culturally sensitive survey instrument and protocols were designed and tested to gather data on lower income, urban African-Americans' use of, attitudes toward, and understanding of CAM. The major findings of this pilot research are 1.) Community-partnered research can help researchers gain access to sensitive data and design culturally appropriate studies; 2.) CAM terminology varies by cultural group; 3.) Certain forms of CAM (folk or family practices) are commonly found in African-American populations; and 4.) Factors that affect CAM use--including age, lack of access to conventional medicine, cultural heritage, and dissatisfaction with conventional medicine.

Ethnic minority use of complementary and alternative medicine (CAM): a national probability survey of CAM utilizers.

CONTEXT: US research results suggest that some sociodemographic characteristics predict use of complementary and alternative medicine (CAM). Specifically, use of CAM has been positively associated with persons from higher socioeconomic status groups and negatively associated with African-Americans. OBJECTIVE: To investigate the sociodemographic characteristics of CAM utilizers in a national probability sample, one containing an over-sampling of ethnic minorities. DESIGN: We tested the hypothesis that CAM use is prevalent among many different ethnic groups in the US. by analyzing a subset of data from The 1995 National Comparative Survey of Minority Health Care of The Commonwealth Fund, a national probability sample of 3,789 persons with an over-sampling of ethnic minorities. The survey was conducted by telephone in 6 languages. We analyzed use of CAM (defined by 5 items: herbal medicine, acupuncture, chiropractic, traditional healer, home remedy) within the last year. RESULTS: Use of 1 or more CAM modalities did not differ by ethnicity. Overall, 43.1% of the respondents reported using 1 or more CAM modality. Predictors of CAM use were female gender, being uninsured, and having a high school education or above. CONCLUSION: Use of CAM is equally prevalent among white, African-American/black, Latino, Asian, and Native American populations in the US, but characteristics of utilizers vary considerably by specific CAM modality.