Using Continuous Passive Assessment Technology to Describe Health and Behavior Patterns Preceding and Following a Cancer Diagnosis in Older Adults: Proof-of-Concept Case Series Study.

BACKGROUND: Describing changes in health and behavior that precede and follow a sentinel health event, such as a cancer diagnosis, is challenging because of the lack of longitudinal, objective measurements that are collected frequently enough to capture varying trajectories of change leading up to and following the event. A continuous passive assessment system that continuously monitors older adults' physical activity, weight, medication-taking behavior, pain, health events, and mood could enable the identification of more specific health and behavior patterns leading up to a cancer diagnosis and whether and how patterns change thereafter. OBJECTIVE: In this study, we conducted a proof-of-concept retrospective analysis, in which we identified new cancer diagnoses in older adults and compared trajectories of change in health and behaviors before and after cancer diagnosis. METHODS: Participants were 10 older adults (mean age 71.8, SD 4.9 years; 3/10, 30% female) with various self-reported cancer types from a larger prospective cohort study of older adults. A technology-agnostic assessment platform using multiple devices provided continuous data on daily physical activity via wearable sensors (actigraphy); weight via a Wi-Fi-enabled digital scale; daily medication-taking behavior using electronic Bluetooth-enabled pillboxes; and weekly pain, health events, and mood with online, self-report surveys. RESULTS: Longitudinal linear mixed-effects models revealed significant differences in the pre- and postcancer trajectories of step counts (P<.001), step count variability (P=.004), weight (P<.001), pain severity (P<.001), hospitalization or emergency room visits (P=.03), days away from home overnight (P=.01), and the number of pillbox door openings (P<.001). Over the year preceding a cancer diagnosis, there were gradual reductions in step counts and weight and gradual increases in pain severity, step count variability, hospitalization or emergency room visits, and days away from home overnight compared with 1 year after the cancer diagnosis. Across the year after the cancer diagnosis, there was a gradual increase in the number of pillbox door openings compared with 1 year before the cancer diagnosis. There was no significant trajectory change from the pre- to post-cancer diagnosis period in terms of low mood (P=.60) and loneliness (P=.22). CONCLUSIONS: A home-based, technology-agnostic, and multidomain assessment platform could provide a unique approach to monitoring different types of behavior and health markers in parallel before and after a life-changing health event. Continuous passive monitoring that is ecologically valid, less prone to bias, and limits participant burden could greatly enhance research that aims to improve early detection efforts, clinical care, and outcomes for people with cancer.

Sex differences in the impact of physical frailty on outcomes in heart failure.

BACKGROUND: Physical frailty is strongly related to adverse outcomes in heart failure (HF), and women are more likely to be physically frail than men; however, it is unknown if this sex difference affects outcomes. OBJECTIVES: To determine if there are sex differences in the associations between physical frailty and health-related quality of life (HRQOL) and clinical outcomes in HF. METHODS: We conducted a prospective study of adults with HF. Physical frailty was assessed using the Frailty Phenotype Criteria. HRQOL was assessed using the Minnesota Living with HF Questionnaire. One-year clinical events (all-cause death or cardiovascular hospitalization or emergency department visit) were ascertained. We used generalized linear modeling to quantify associations between physical frailty and HRQOL, and Cox proportional hazards modeling to quantify associations between physical frailty and clinical events, adjusting for Seattle HF Model scores. RESULTS: The sample (n = 115) was 63.5 ± 15.7 years old and 49% women. Physical frailty was associated with significantly worse total HRQOL among women (p = 0.005) but not men (p = 0.141). Physical frailty was associated with worse physical HRQOL among both women (p < 0.001) and men (p = 0.043). There was a 46% higher clinical event risk for every one-point increase in physical frailty score among men (p = 0.047) but not women (p = 0.361). CONCLUSIONS: Physical frailty is associated with worse overall HRQOL among women and higher clinical event risk among men, indicating a need to better understand contributors to sex-specific health differences associated with physical frailty in HF.

Qualitative Impressions of a Yoga Nidra Practice for Insomnia: An Exploratory Mixed-Methods Design.

Introduction: Insomnia affects up to half of the U.S. population, and due to limitations of current treatments, there is a growing interest in mind-body practices to reduce insomnia. To understand how a guided meditation practice, Yoga Nidra, may affect relaxation and align with current descriptions of nonpharmaceutical practices that could improve sleep, qualitative and quantitative methods were used to explore participant experience of a single Yoga Nidra practice, administered in a group setting. Methods: Current insomnia (Insomnia Severity Index), sleep practices, and mood (positive and negative affect schedule [PANAS]) were measured at intake. After 30 min of Yoga Nidra practice, the PANAS was readministered. In a focus group that followed, participants discussed their experience before, during, and after the practice and the likelihood of repeating it. Six groups were conducted. All interested adults were welcome to join. Results: In the final sample of 33 individuals (79% female), 80% of participants reported insomnia at intake and 45% reported a regular mind-body practice, supporting the prevalence of insomnia in the society as well as the interest in mind-body practices. After the Yoga Nidra intervention, mean negative affect decreased 5.6 ± 4.5 points, a 31% decrease from baseline, and positive affect decreased 3.5 ± 9.7 points, a 13% decrease. Three major themes were identified from focus group discussions: response to the practice (relaxation, perceived sleep, and sense withdrawal); factors that affect engagement (delivery method and intrapersonal factors); and potential as a clinical intervention (for conditions including sleep, anxiety, and pain). Conclusion: Yoga Nidra appeared tolerable within the sample, and descriptions suggest it may be useful for enhancing relaxation, facilitating sleep, easing anxiety, and reducing pain. Results from this study will inform the design of future studies of Yoga Nidra for insomnia and related conditions.

Program evaluation of trauma-informed yoga for vulnerable populations.

BACKGROUND: Trauma is highly prevalent among vulnerable populations, including those who are incarcerated, in treatment for substance use, or seeking mental health services. Trauma-informed yoga seeks to create a safer yoga practice for individuals with a trauma history and may improve emotional and physical wellbeing. Thus, we conducted an evaluation of a trauma-informed yoga program to gain insight into participant experiences. METHODS: Trauma-informed yoga classes were led by trained volunteers and held in three sectors that work with vulnerable populations: corrections and reentry, substance use treatment and recovery, and community and mental health. Data were collected via anonymous survey using a retrospective pre-post design. The survey instrument captured reasons for student participation and perceived effects of yoga on emotional and physical wellbeing. RESULTS: Students were motivated to participate in yoga classes by expectations of physical, mental, and spiritual benefit. Students reported perceived improvements in emotional and physical wellbeing and greater use of self-regulation skills after starting yoga. CONCLUSION: Our findings suggest trauma-informed yoga is perceived as beneficial by vulnerable individuals, especially those in the correctional system or recovering from substance use. Our results support the value of offering trauma-informed yoga in institutionalized and community settings. Improvements in emotional and physical wellbeing warrant formal study.

Effects of Hydrastis Canadensis, Commiphora Habessinica, Phytolacca Americana, and Echinacea Purpurea on Bacterial Growth.

CONTEXT: With the rise of antibiotic resistance, new strategies are needed to treat minor bacterial infections so that conventional antibiotics may be reserved for more serious conditions. One herbal formula, known as the HMPE formula, is often prescribed for minor infections. It includes Hydrastis canadensis (H. canadensis), Commiphora habessinica (C. habessinica), Phytolacca americana (P. americana), and Echinacea purpurea (E. purpurea). These herbs offer promise as treatments that may inhibit bacterial growth and stimulate the immune system. OBJECTIVE: To investigate the antibacterial effects of the HMPE formula and its constituent herbs against two organisms, Staphylococcus epidermidis and Escherichia coli. DESIGN: The research team performed an in-vitro study. SETTING: The study occurred at the Helfgott Research Institute at the National University of Natural Medicine in Portland, OR, USA. INTERVENTION: The study tested HMPE and each of its ingredients alone for antibacterial properties. OUTCOME MEASURES: The outcome measure was a disc diffusion assay. Sterile paper discs were impregnated with 15 µl of E. purpurea, H. canadensis, C. habessinica , or P. americana as herbal tinctures; with the complete HMPE formula; or with 65% ethanol as the negative control, and dried at room temperature for 40 minutes. Commercially prepared 10 µg ampicillin discs were used as a positive control. RESULTS: H. Canadensis and, to a lesser extent, the complete HMPE formula significantly inhibited the growth of the gram-positive bacteria Staphylococcus epidermidis, but not the gram-negative bacteria Escherichia coli. C. habessinica, P. americana, and E. purpurea alone did not inhibit growth of either bacterial strain. CONCLUSIONS: The results demonstrated that H. canadensis had antibacterial activity against S. epidermidis, but the HMPE formula was not active against S. epidermidis, when a zone of inhibition threshold of 12 millimeters (mm) was used to determine antibiotic activity. Because the HMPE formula was shown to be less effective than H. canadensis alone, the formula might benefit from an increased percentage of H. canadensis.

Effects of Methylsulfonylmethane (MSM) on exercise-induced oxidative stress, muscle damage, and pain following a half-marathon: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Oxidative stress and muscle damage occur during exhaustive bouts of exercise, and many runners report pain and soreness as major influences on changes or breaks in training regimens, creating a barrier to training persistence. Methylsulfonylmethane (MSM) is a sulfur-based nutritional supplement that is purported to have pain and inflammation-reducing effects. To investigate the effects of MSM in attenuating damage associated with physical exertion, this randomized, double-blind, placebo-controlled study evaluated the effects of MSM supplementation on exercise-induced pain, oxidative stress and muscle damage. METHODS: Twenty-two healthy females (n = 17) and males (n = 5) (age 33.7 ± 6.9 yrs.) were recruited from the 2014 Portland Half-Marathon registrant pool. Participants were randomized to take either MSM (OptiMSM®) (n = 11), or a placebo (n = 11) at 3 g/day for 21 days prior to the race and for two days after (23 total). Participants provided blood samples for measurement of markers of oxidative stress, and completed VAS surveys for pain approximately one month prior to the race (T0), and at 15 min (T1), 90 min (T2), 1 Day (T3), and 2 days (T4) after race finish. The primary outcome measure 8-hydroxy-2-deoxyguanine (8-OHdG) measured oxidative stress. Secondary outcomes included malondialdehyde (MDA) for oxidative stress, creatine kinase (CK) and lactate dehydrogenase (LDH) as measures of muscle damage, and muscle (MP) and joint pain (JP) recorded using a 100 mm Visual Analogue Scale (VAS). Data were analyzed using repeated and multivariate ANOVAs, and simple contrasts compared post-race time points to baseline, presented as mean (SD) or mean change (95% CI) where appropriate. RESULTS: Running a half-marathon induced significant increases in all outcome measures (p < 0.001). From baseline, 8-OHdG increased significantly at T1 by 1.53 ng/mL (0.86-2.20 ng/mL CI, p < 0.001) and T2 by 1.19 ng/mL (0.37-2.01 ng/mL CI, p < 0.01), and fell below baseline levels at T3 by -0.46 ng/mL (-1.18-0.26 CI, p > 0.05) and T4 by -0.57 ng/mL (-1.27-0.13 CI, p > 0.05). MDA increased significantly at T1 by 7.3 µM (3.9-10.7 CI, p < 0.001). Muscle damage markers CK and LDH saw significant increases from baseline at all time-points (p < 0.01). Muscle and joint pain increased significantly from baseline at T1, T2, and T3 (p < 0.01) and returned to baseline levels at T4. Time-by-treatment results did not reach statistical significance for any outcome measure, however, the MSM group saw clinically significant (Δ > 10 mm) reductions in both muscle and joint pain. CONCLUSION: Participation in a half-marathon was associated with increased markers of oxidative stress, muscle damage, and pain. MSM supplementation was not associated with a decrease from pre-training levels of oxidative stress or muscle damage associated with an acute bout of exercise. MSM supplementation attenuated post-exercise muscle and joint pain at clinically, but not statistically significant levels.

Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia.

Recent evidence suggests that inhibition of protein phosphatase 2A (PP2A) tumor suppressor activity via the SET oncoprotein contributes to the pathogenesis of various cancers. Here we demonstrate that both SET and c-MYC expression are frequently elevated in T-ALL cell lines and primary samples compared to healthy T cells. Treatment of T-ALL cells with the SET antagonist OP449 restored the activity of PP2A and reduced SET interaction with the PP2A catalytic subunit, resulting in a decrease in cell viability and c-MYC expression in a dose-dependent manner. Since a tight balance between phosphatases and kinases is required for the growth of both normal and malignant cells, we sought to identify a kinase inhibitor that would synergize with SET antagonism. We tested various T-ALL cell lines against a small-molecule inhibitor screen of 66 compounds targeting two-thirds of the tyrosine kinome and found that combined treatment of T-ALL cells with dovitinib, an orally active multi-targeted small-molecule receptor tyrosine kinase inhibitor, and OP449 synergistically reduced the viability of all tested T-ALL cell lines. Mechanistically, combined treatment with OP449 and dovitinib decreased total and phospho c-MYC levels and reduced ERK1/2, AKT, and p70S6 kinase activity in both NOTCH-dependent and independent T-ALL cell lines. Overall, these results suggest that combined targeting of tyrosine kinases and activation of serine/threonine phosphatases may offer novel therapeutic strategies for the treatment of T-ALL.

Curriculum Development of a Research Laboratory Methodology Course for Complementary and Integrative Medicine Students.

Training in fundamental laboratory methodologies is valuable to medical students because it enables them to understand the published literature, critically evaluate clinical studies, and make informed decisions regarding patient care. It also prepares them for research opportunities that may complement their medical practice. The National College of Natural Medicine's (NCNM) Master of Science in Integrative Medicine Research (MSiMR) program has developed an Introduction to Laboratory Methods course. The objective of the course it to train clinical students how to perform basic laboratory skills, analyze and manage data, and judiciously assess biomedical studies. Here we describe the course development and implementation as it applies to complementary and integrative medicine students.

The Axin1 scaffold protein promotes formation of a degradation complex for c-Myc.

Expression of the c-Myc proto-oncoprotein is tightly regulated in normal cells. Phosphorylation at two conserved residues, threonine58 (T58) and serine62 (S62), regulates c-Myc protein stability. In cancer cells, c-Myc can become aberrantly stabilized associated with altered T58 and S62 phosphorylation. A complex signalling cascade involving GSK3beta kinase, the Pin1 prolyl isomerase, and the PP2A-B56alpha phosphatase controls phosphorylation at these sites. We report here a novel role for the tumour suppressor scaffold protein Axin1 in facilitating the formation of a degradation complex for c-Myc containing GSK3beta, Pin1, and PP2A-B56alpha. Although knockdown of Axin1 decreases the association of c-Myc with these proteins, reduces T58 and enhances S62 phosphorylation, and increases c-Myc stability, acute expression of Axin1 reduces c-Myc levels and suppresses c-Myc transcriptional activity. Moreover, the regulation of c-Myc by Axin1 is impaired in several tested cancer cell lines with known stabilization of c-Myc or loss of Axin1. This study provides critical insight into the regulation of c-Myc expression, how this can be disrupted in three cancer types, and adds to our knowledge of the tumour suppressor activity of Axin1.

FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.

gamma-secretase inhibitors (GSIs) can block NOTCH receptor signaling in vitro and therefore offer an attractive targeted therapy for tumors dependent on deregulated NOTCH activity. To clarify the basis for GSI resistance in T cell acute lymphoblastic leukemia (T-ALL), we studied T-ALL cell lines with constitutive expression of the NOTCH intracellular domain (NICD), but that lacked C-terminal truncating mutations in NOTCH1. Each of the seven cell lines examined and 7 of 81 (8.6%) primary T-ALL samples harbored either a mutation or homozygous deletion of the gene FBW7, a ubiquitin ligase implicated in NICD turnover. Indeed, we show that FBW7 mutants cannot bind to the NICD and define the phosphodegron region of the NICD required for FBW7 binding. Although the mutant forms of FBW7 were still able to bind to MYC, they do not target it for degradation, suggesting that stabilization of both NICD and its principle downstream target, MYC, may contribute to transformation in leukemias with FBW7 mutations. In addition, we show that all seven leukemic cell lines with FBW7 mutations were resistant to the MRK-003 GSI. Most of these resistant lines also failed to down-regulate the mRNA levels of the NOTCH targets MYC and DELTEX1 after treatment with MRK-003, implying that residual NOTCH signaling in T-ALLs with FBW7 mutations contributes to GSI resistance.

Uniform adherent neural progenitor populations from rhesus embryonic stem cells.

Rhesus and human embryonic stem cells (ESCs) are similar, making rhesus ESCs an appropriate preclinical allograft model for refining stem cell therapies. Use of rhesus ESC-derived neural progenitors (NPs) in preclinical applications will be enhanced if the neural derivation process is scalable and free from contaminating ESCs or nonneural cells. In this study, we have quantified temporal gene expression changes of rhesus ESC differentiated to uniform NPs using simple feeder-free adherent cultures. NPs exhibited a significant up-regulation of neural-specific genes and a downregulation of pluripotency genes. Additionally, expression of Hu, MAP2, and Tuj1, shows that NPs can form post-mitotic neurons. This study represents a simple and scalable means of producing adherent primate NPs for preclinical testing of neural cell-based therapy.

Long-term proliferation of human embryonic stem cell-derived neuroepithelial cells using defined adherent culture conditions.

Research on the cell fate determination of embryonic stem cells is of enormous interest given the therapeutic potential in regenerative cell therapy. Human embryonic stem cells (hESCs) have the ability to renew themselves and differentiate into all three germ layers. The main focus of this study was to examine factors affecting derivation and further proliferation of multipotent neuroepithelial (NEP) cells from hESCs. hESCs cultured in serum-deprived defined medium developed distinct tube structures and could be isolated either by dissociation or adherently. Dissociated cells survived to form colonies of cells characterized as NEP when conditioned medium from human hepatocellular carcinoma HepG2 cell line (MEDII) was added. However, cells isolated adherently developed an enriched population of NEP cells independent of MEDII medium. Further characterization suggested that they were NEP cells because they had a similar phenotype profile to in vivo NEP cells and expression SOX1, SOX2, and SOX3 genes. They were positive for Nestin, a neural intermediate filament protein, and Musashi-1, a neural RNA-binding protein, but few cells expressed further differentiation markers, such as PSNCAM, A2B5, MAPII, GFAP, or O4, or other lineage markers, such as muscle actin, alpha fetoprotein, or the pluripotent marker Oct4. Further differentiation of these putative NEP cells gave rise to a mixed population of progenitors that included A2B5-positive and PSNCAM-positive cells and postmitotic neurons and astrocytes. To proliferate and culture these derived NEP cells, ideal conditions were obtained using neurobasal medium supplemented with B27 and basic fibroblast growth factor in 5% oxygen. NEP cells were continuously propagated for longer than 6 months without losing their multipotent cell characteristics and maintained a stable chromosome number.

Integration of Cot analysis, DNA cloning, and high-throughput sequencing facilitates genome characterization and gene discovery.

Cot-based sequence discovery represents a powerful means by which both low-copy and repetitive sequences can be selectively and efficiently fractionated, cloned, and characterized. Based upon the results of a Cot analysis, hydroxyapatite chromatography was used to fractionate sorghum (Sorghum bicolor) genomic DNA into highly repetitive (HR), moderately repetitive (MR), and single/low-copy (SL) sequence components that were consequently cloned to produce HRCot, MRCot, and SLCot genomic libraries. Filter hybridization (blotting) and sequence analysis both show that the HRCot library is enriched in sequences traditionally found in high-copy number (e.g., retroelements, rDNA, centromeric repeats), the SLCot library is enriched in low-copy sequences (e.g., genes and "nonrepetitive ESTs"), and the MRCot library contains sequences of moderate redundancy. The Cot analysis suggests that the sorghum genome is approximately 700 Mb (in agreement with previous estimates) and that HR, MR, and SL components comprise 15%, 41%, and 24% of sorghum DNA, respectively. Unlike previously described techniques to sequence the low-copy components of genomes, sequencing of Cot components is independent of expression and methylation patterns that vary widely among DNA elements, developmental stages, and taxa. High-throughput sequencing of Cot clones may be a means of "capturing" the sequence complexity of eukaryotic genomes at unprecedented efficiency.