I am a member and former Chair of the Department of Health Promotion, in the School of Public Health, in the Faculty of Medicine at Tel-Aviv University, former director, and founder of the Integrative Medicine Center & Research Laboratory at the Tel- Aviv Medical Center, and Head of the Health Promotion Unit in the Integrated Cancer Prevention Center. My training is in cellular biology, integrative medicine, intervention research, and health promotion science. I received the Outstanding Israeli Researcher for Complementary and Integrative Medicine award. The goal of my research is to unravel the biology, physiology, and psychology of health promotion approaches and translate findings into interventions that effectively target salutogenic mechanisms underpinning the biopsychology of well-being. I initiated the "lasting change" study and will co-lead this project in my current role as visiting scholar, at Prof. Michael Snyder's Lab, a global leader in precision health at Stanford University.

Academic Appointments

All Publications

  • Using Ecological Momentary Assessments to Study How Daily Fluctuations in Psychological States Impact Stress, Well-Being, and Health. Journal of clinical medicine Mengelkoch, S., Moriarity, D. P., Novak, A. M., Snyder, M. P., Slavich, G. M., Lev-Ari, S. 2023; 13 (1)


    Despite great interest in how dynamic fluctuations in psychological states such as mood, social safety, energy, present-focused attention, and burnout impact stress, well-being, and health, most studies examining these constructs use retrospective assessments with relatively long time-lags. Here, we discuss how ecological momentary assessments (EMAs) address methodological issues associated with retrospective reports to help reveal dynamic associations between psychological states at small timescales that are often missed in stress and health research. In addition to helping researchers characterize daily and within-day fluctuations and temporal dynamics between different health-relevant processes, EMAs can elucidate mechanisms through which interventions reduce stress and enhance well-being. EMAs can also be used to identify changes that precede critical health events, which can in turn be used to deliver ecological momentary interventions, or just-in-time interventions, to help prevent such events from occurring. To enable this work, we provide examples of scales and single-item questions used in EMA studies, recommend study designs and statistical approaches that capitalize on EMA data, and discuss limitations of EMA methods. In doing so, we aim to demonstrate how, when used carefully, EMA methods are well poised to greatly advance our understanding of how intrapersonal dynamics affect stress levels, well-being, and human health.

    View details for DOI 10.3390/jcm13010024

    View details for PubMedID 38202031

  • Mental Health for All: The Case for Investing in Digital Mental Health to Improve Global Outcomes, Access, and Innovation in Low-Resource Settings. Journal of clinical medicine Faria, M., Zin, S. T., Chestnov, R., Novak, A. M., Lev-Ari, S., Snyder, M. 2023; 12 (21)


    Mental health disorders are an increasing global public health concern that contribute to morbidity, mortality, disability, and healthcare costs across the world. Biomedical and psychological research has come a long way in identifying the importance of mental health and its impact on behavioral risk factors, physiological health, and overall quality of life. Despite this, access to psychological and psychiatric services remains widely unavailable and is a challenge for many healthcare systems, particularly those in developing countries. This review article highlights the strengths and opportunities brought forward by digital mental health in narrowing this divide. Further, it points to the economic and societal benefits of effectively managing mental illness, making a case for investing resources into mental healthcare as a larger priority for large non-governmental organizations and individual nations across the globe.

    View details for DOI 10.3390/jcm12216735

    View details for PubMedID 37959201

  • Data From a One-Stop-Shop Comprehensive Cancer Screening Center JOURNAL OF CLINICAL ONCOLOGY Bernstein, E., Lev-Ari, S., Shapira, S., Leshno, A., Sommer, U., Al-Shamsi, H., Shaked, M., Segal, O., Galazan, L., Hay-Levy, M., Sror, M., Harlap-Gat, A., Peer, M., Moshkowitz, M., Wolf, I., Liberman, E., Shenberg, G., Gur, E., Elran, H., Melinger, G., Mashiah, J., Isakov, O., Zrifin, E., Gluck, N., Dekel, R., Kleinman, S., Aviram, G., Blachar, A., Kessler, A., Golan, O., Geva, R., Yossepowitch, O., Neugut, A. I., Arber, N. 2023; 41 (14): 2503-+


    Cancer is the second leading cause of death globally. However, by implementing evidence-based prevention strategies, 30%-50% of cancers can be detected early with improved outcomes. At the integrated cancer prevention center (ICPC), we aimed to increase early detection by screening for multiple cancers during one visit.Self-referred asymptomatic individuals, age 20-80 years, were included prospectively. Clinical, laboratory, and epidemiological data were obtained by multiple specialists, and further testing was obtained based on symptoms, family history, individual risk factors, and abnormalities identified during the visit. Follow-up recommendations and diagnoses were given as appropriate.Between January 1, 2006, and December 31, 2019, 8,618 men and 8,486 women, average age 47.11 ± 11.71 years, were screened. Of 259 cancers detected through the ICPC, 49 (19.8%) were stage 0, 113 (45.6%) stage I, 30 (12.1%) stage II, 25 (10.1%) stage III, and 31(12.5%) stage IV. Seventeen cancers were missed, six of which were within the scope of the ICPC. Compared with the Israeli registry, at the ICPC, less cancers were diagnosed at a metastatic stage for breast (none v 3.7%), lung (6.7% v 11.4%), colon (20.0% v 46.2%), prostate (5.6% v 10.5%), and cervical/uterine (none v 8.5%) cancers. When compared with the average stage of detection in the United States, detection was earlier for breast, lung, prostate, and female reproductive cancers. Patient satisfaction rate was 8.35 ± 1.85 (scale 1-10).We present a proof of concept study for a one-stop-shop approach to cancer screening in a multidisciplinary outpatient clinic. We successfully detected cancers at an early stage, which has the potential to reduce morbidity and mortality as well as offer substantial cost savings.[Media: see text].

    View details for DOI 10.1200/JCO.22.00938

    View details for Web of Science ID 001009704600011

    View details for PubMedID 36669135

  • Distress following the COVID-19 Pandemic among Schools' Stakeholders: Psychosocial Aspects and Communication. International journal of environmental research and public health Kaim, A., Lev-Ari, S., Adini, B. 2023; 20 (6)


    In response to the COVID-19 pandemic, many governments ordered school closures as a containment measure, with Israel being among over 100 countries to do so. This resulted in the abrupt shift to online and remote education for many students. Despite attempts to minimize the effects of disrupted education and create a dynamic virtual learning environment, the literature highlights various challenges including lack of communication with implications of distress faced by key stakeholders (students and their parents, teachers, and principals). In this cross-sectional study, we assess the perceived levels of communication and psychosocial aspects during both distance and frontal learning, as well as the long-term impacts (following over two and a half years of an ongoing pandemic) on distress among the key stakeholders of the Israeli education system- high school students, parents, teachers, and principals. The study findings demonstrate severe implications of distance learning on communication and psychosocial aspects, with lingering long-term impacts on distress, among all stakeholders (particularly among students). This reveals the need for tailored capacity building and resilience intervention programs to be integrated in the long-term response to the current ongoing pandemic to improve well-being and reduce distress among the various stakeholders, with particular attention to those that are most vulnerable and were hit the hardest.

    View details for DOI 10.3390/ijerph20064837

    View details for PubMedID 36981747

  • Resilience, Stress, Well-Being, and Sleep Quality in Multiple Sclerosis JOURNAL OF CLINICAL MEDICINE Novak, A., Lev-Ari, S. 2023; 12 (2)


    (1) Background: Multiple Sclerosis (MS) is a chronic, progressive, immune-mediated disorder that affects the Central Nervous System and is the most common cause of non-traumatic neurological disability in young adults. The study aimed to assess the levels of stress, resilience, well-being, sleep quality, and fatigue in Israeli people with MS (PwMS), and to examine the associations between these factors and the sociodemographic and clinical characteristics. These factors had never before been studied in conjunction in PwMS, nor had they been systematically addressed in Israel, the unique geopolitical situation of which may pose unique challenges. (2) Methods: This was a survey-based, cross-sectional study conducted through an Internet platform. (3) Results: Israeli PwMS who participated in the study were experiencing relatively high levels of stress and low resilience, poor sleep quality, and severe fatigue. The analysis revealed significant associations between resilience and stress, well-being, and anxiety, as well as stress and well-being, resilience, sleep quality, fatigue, and Clinically Isolated Syndrome (CIS). (4) Conclusions: the Israeli PwMS who participated in the study were experiencing higher levels of stress, lower resilience and worse sleep quality than PwMS in other countries, as compared to results previously reported in literature. The findings of this study ought to serve as a call to action for the MS care providers in Israel and warrant further research into the possible causes of the phenomenon and strategies to address it.

    View details for DOI 10.3390/jcm12020716

    View details for Web of Science ID 000914277200001

    View details for PubMedID 36675644

    View details for PubMedCentralID PMC9864697

  • The Use of Smart Devices for Mental Health Diagnosis and Care. Journal of clinical medicine Lautman, Z., Lev-Ari, S. 2022; 11 (18)


    In 2019, more than 970 million people worldwide suffered from a mental disorder, with anxiety and depressive disorders as the leading culprits [...].

    View details for DOI 10.3390/jcm11185359

    View details for PubMedID 36143004

    View details for PubMedCentralID PMC9501104

  • A novel platform for attenuating immune hyperactivity using EXO-CD24 in COVID-19 and beyond EMBO MOLECULAR MEDICINE Shapira, S., Ben Shimon, M., Hay-Levi, M., Shenberg, G., Choshen, G., Bannon, L., Tepper, M., Kazanov, D., Seni, J., Lev-Ari, S., Peer, M., Boubas, D., Stebbing, J., Tsiodras, S., Arber, N. 2022; 14 (9): e15997


    A small but significant proportion of COVID-19 patients develop life-threatening cytokine storm. We have developed a new anti-inflammatory drug, EXO-CD24, a combination of an immune checkpoint (CD24) and a delivery platform (exosomes). CD24 inhibits the NF-kB pathway and the production of cytokines/chemokines. EXO-CD24 discriminates damage-from pathogen-associated molecular patterns (DAMPs and PAMPs) therefore does not interfere with viral clearance. EXO-CD24 was produced and purified from CD24-expressing 293-TREx™ cells. Exosomes displaying murine CD24 (mCD24) were also created. EXO-CD24/mCD24 were characterized and examined, for safety and efficacy, in vitro and in vivo. In a phase Ib/IIa study, 35 patients with moderate-high severity COVID-19 were recruited and given escalating doses, 108 -1010 , of EXO-CD24 by inhalation, QD, for 5 days. No adverse events related to the drug were observed up to 443-575 days. EXO-CD24 effectively reduced inflammatory markers and cytokine/chemokine, although randomized studies are required. EXO-CD24 may be a treatment strategy to suppress the hyper-inflammatory response in the lungs of COVID-19 patients and further serve as a therapeutic platform for other pulmonary and systemic diseases characterized by cytokine storm.

    View details for DOI 10.15252/emmm.202215997

    View details for Web of Science ID 000823702400001

    View details for PubMedID 35776000

    View details for PubMedCentralID PMC9349550

  • The Association between the Sense of Coherence and the Self-Reported Adherence to Guidelines during the First Months of the COVID-19 Pandemic in Israel INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH Novak, A., Katz, A., Bitan, M., Lev-Ari, S. 2022; 19 (13)


    (1) Background: Social distancing became a central strategy employed to limit the spread of the SARS-CoV-2 virus. We explore self-reported adherence (SRA) and factors associated with SRA among Israeli adults at the end of the first national lockdown in Israel. (2) Methods: We conducted a cross-sectional consumer panel survey of 820 Israeli adults aged 18 to 70 in May and June 2020. We collected data on the SRA to the social distancing measures, sociodemographic variables, perceptions of pandemic-related danger and of protection provided by the social distancing measures, as well as Sense of Coherence (SoC). (3) Results: 60% of respondents reported complying with 7 measures. Higher SoC was associated with higher SRA (p = 0.04), and was related to income, marital status, age, profession, and education. The SRA was higher among Jews than Arabs (Jews: Mean = 10.5, SD = 4.5; Arabs: Mean = 9.1, SD = 4.1, p < 0.001) and among males (Males: Mean = 10.8, SD = 4.7; Females: Mean = 9, SD = 4.1; p = 0.003). SoC, perception of protection and perception of danger were associated with higher SRA (p = 0.42, p < 0.001 and p = 0.005 respectively). Single people reported higher levels of SRA than people in relationships (Partnered: Mean = 9.7, SD = 4.2, Non-partnered: Mean = 10.9, SD = 4.7, p = 0.033). (4) Conclusions: At the time of exit from the first lockdown, compliance with social distancing measures was high, with Jewish, single and male Israelis more likely to adhere to the guidelines. We identified the populations at risk for non-adherence and associated factors, reporting for the first time the correlation between SoC and SRA. Further research is needed to assess the role of these factors in Jewish and Arab populations.

    View details for DOI 10.3390/ijerph19138041

    View details for Web of Science ID 000824689400001

    View details for PubMedID 35805697

    View details for PubMedCentralID PMC9265674

  • Age Differences in Recovery Rate Following an Aerobic-Based Exercise Protocol Inducing Muscle Damage Among Amateur, Male Athletes FRONTIERS IN PHYSIOLOGY Markus, I., Constantini, K., Goldstein, N., Amedi, R., Bornstein, Y., Stolkovsky, Y., Vidal, M., Lev-Ari, S., Balaban, R., Leibou, S., Blumenfeld-Katzir, T., Ben-Eliezer, N., Peled, D., Assaf, Y., Jensen, D., Constantini, N., Dubnov-Raz, G., Halperin, I., Gepner, Y. 2022; 13: 916924


    Purpose: Compare recovery rates between active young (Y) and middle-aged (MA) males up to 48H post aerobically based, exercise-induced muscle damage (EIMD) protocol. A secondary aim was to explore the relationships between changes in indices associated with EIMD and recovery throughout this timeframe. Methods: Twenty-eight Y (n = 14, 26.1 ± 2.9y, 74.5 ± 9.3 kg) and MA (n = 14, 43.6 ± 4.1y, 77.3 ± 12.9 kg) physically active males, completed a 60-min downhill running (DHR) on a treadmill at -10% incline and at 65% of maximal heart rate (HR). Biochemical, biomechanical, psychological, force production and muscle integrity (using MRI diffusion tensor imaging) markers were measured at baseline, immediately-post, and up to 48H post DHR. Results: During the DHR, HR was lower (p < 0.05) in MA compared to Y, but running pace and distance covered were comparable between groups. No statistical or meaningful differences were observed between groups for any of the outcomes. Yet, Significant (p < 0.05) time-effects within each group were observed: markers of muscle damage, cadence and perception of pain increased, while TNF-a, isometric and dynamic force production and stride-length decreased. Creatine-kinase at 24H-post and 48H-post were correlated (p < 0.05, r range = -0.57 to 0.55) with pain perception, stride-length, and cadence at 24H-post and 48H-post. Significant (p < 0.05) correlations were observed between isometric force production at all time-points and IL-6 at 48H-post DHR (r range = -0.62 to (-0.74). Conclusion: Y and MA active male amateur athletes recover in a comparable manner following an EIMD downhill protocol. These results indicate that similar recovery strategies can be used by trainees from both age groups following an aerobic-based EIMD protocol.

    View details for DOI 10.3389/fphys.2022.916924

    View details for Web of Science ID 000823246100001

    View details for PubMedID 35774290

    View details for PubMedCentralID PMC9239318

  • Effect of Inquiry-Based Stress Reduction on Well-being and Views on Risk-Reducing Surgery Among Women With BRCA Variants in Israel: A Randomized Clinical Trial. JAMA network open Landau, C., Novak, A. M., Ganz, A. B., Rolnik, B., Friedman, E., Lev-Ari, S. 1800; 4 (12): e2139670


    Importance: The high risk for breast and ovarian cancers conferred by being a carrier of BRCA1 or BRCA2 germline variant can negatively impact physical and psychological well-being. Novel nonpharmacological interventions on well-being in women with BRCA variants have rarely been reported.Objective: To determine the effect of a 12-week inquiry-based stress reduction (IBSR) program on psychological well-being, sleep quality, psychosocial variables, and attitudes toward risk-reducing surgical procedures among women in Israel who carried BRCA variants.Design, Setting, and Participants: This randomized clinical trial had a 12-week intervention period and a 12-week follow-up period. It was conducted between April 1, 2017, and July 31, 2020. Participants were recruited from the Meirav Breast Center at the Sheba Medical Center, Israel, and the intervention was conducted in Tel Aviv, Israel. The cohort included women with BRCA variants. Data were analyzed from August 1 to December 1, 2020.Interventions: Women were randomly assigned to the 12-week IBSR program or standard care. The IBSR technique is based on the skills of mindfulness, inquiry, and cognitive reframing. The intervention included standardized, weekly group meetings conducted throughout 12 weeks. Standard care included semi-annual breast examinations and breast magnetic resonance imaging (alternating), a gynecological examination, a transvaginal ultrasonographic examination, and CA-125 serum determination. Differences between the groups were tested using mixed-effects models in an intent to treat analysis.Main Outcomes and Measures: The primary outcome was psychological well-being, including 6 parameters: autonomy, personal growth, positive relationships, control of the environment, goals in life, and self-acceptance. Secondary outcomes included sleep quality, attitudes toward risk-reducing surgical procedures, and psychosocial variables. Questionnaires were administered at baseline (T1), at completion of the 12-week intervention (T2), and 12 weeks after completion of the intervention (T3).Results: Overall, 100 women (mean [SD] age, 41.37 [11.06] years) completed the study, with 50 randomized to the intervention group and 50 randomized to the control group. Mean (SD) time from variant discovery was 4.7 (3.3) years. There were no differences between the intervention and control groups in baseline mean (SD) scores of psychological well-being parameters (autonomy: 55.20 [11.12] vs 56.77 [9.90]; environmental control: 56.30 [11.98 vs 58.51 [11.41]; positive relationships: 63.10 [15.91] vs 68.10 [9.86]; goals in life: 60.00 [14.12] vs 64.82 [10.57]; self-acceptance: 55.02 [16.62] vs 60.32 [13.50]) except personal growth (63.70 [14.66] vs 68.85 [8.07]). The IBSR group, compared with the control group, experienced better mean (SD) scores on all psychological well-being parameters at T2 (autonomy: 63.64 [8.35] vs 54.73 [10.41]; environmental control: 63.95 [10.05] vs 57.45 [11.43]; personal growth: 73.00 [8.34] vs 65.76 [10.95]; positive relationships 71.17 [9.99] vs 65.06 [12.58]; goals in life: 67.57 [8.88] vs 61.18 [12.87]; self-acceptance: 66.93 [11.15] vs 58.09 [15.55]) and at T3 (autonomy: 62.68 [9.05] vs 56.12 [10.64]; environmental control: 64.55 [10.28] vs 59.35 [12.98]; personal growth: 72.00 [8.06] vs 67.15 [11.82]; positive relationships: 71.24 [9.78] vs 66.92 [12.37]; goals in life: 68.33 [8.54] vs 62.92 [13.24]; self-acceptance: 66.84 [11.35] vs 58.97 [17.03]). Individuals in the IBSR group also experienced statistically significant improvements in sleep quality (mean [SD]: T1, 7.35 [3.97]; T3, 4.63 [3.21], P<.001), whereas the control group experienced no statistically significant difference. Women in the intervention group had a more favorable consideration of risk-reducing oophorectomy, from 7 women (14%) who refused to consider oophorectomy at T1 to 1 woman (2%) who refused to consider it at T3 (P=.04), and similar change in consideration of mastectomy: from 23 women (46%) who refused to consider mastectomy at T1 to 13 women (29%) who refused to consider it at T3 (P<.001).Conclusions and Relevance: This randomized clinical trial found that IBSR improved psychological well-being and led to a more favorable view on risk-reducing surgical procedures for at least 6 months among women in Israel who carried BRCA variants. These results suggest that IBSR may be implemented as a self-practice tool to enhance the well-being of individuals who carry BRCA variants and support them in their decision-making processes.Trial Registration: Identifier: NCT03162276.

    View details for DOI 10.1001/jamanetworkopen.2021.39670

    View details for PubMedID 34962562

  • Reaching 80 Years of Age: Clinical, Behavioral, and Psychosocial Related Risk Factors in a Large Cohort of Israeli Working Men JOURNAL OF CLINICAL MEDICINE Lev-Ari, S., Novak, A., Zemer, A., Gerber, Y., Goldbourt, U. 2021; 10 (23)


    The objective of this study was to estimate the probability of long-term overall survival based on total number of risk factors (RF). We also sought to examine the role of midlife clinical, behavioral, and psychosocial predictors of longevity in a large cohort of Israeli men. This study was based on the Israeli Ischemic Heart Disease (IIHD) cohort that included over 10,000 men who were followed up for mortality over more than four decades. During the 43 years of follow-up, 4634 (46.1%) men survived to 80 years of age or older. We considered cigarette smoking, diabetes mellitus, high systolic blood pressure, hypercholesterolemia, low socioeconomic status, and serious family problems as RF at ages 40-65. Cox proportional hazards regression models, with age as the time scale, were constructed to estimate the hazard ratios (HRs) for failure to survive 80 years of age. Compared with men free of all the above RF, those with one identified RF (HR = 1.58, 95% CI: 1.42-1.75) and counterparts with two identified RF (HR = 2.18, 95% CI: 1.96-2.43) were at a significantly greater risk of death before 80. Additional RF further increased the risk of early mortality (HR = 3.62, 95% CI: 1.50-8.73 for men with 5 RF). The results suggest a role of physiological, behavioral, and psychological risk factors at midlife in predicting longevity.

    View details for DOI 10.3390/jcm10235706

    View details for Web of Science ID 000735021500001

    View details for PubMedID 34884408

    View details for PubMedCentralID PMC8658640

  • Mindfulness-Based Stress Reduction Increases Mental Wellbeing and Emotion Regulation During the First Wave of the COVID-19 Pandemic: A Synchronous Online Intervention Study FRONTIERS IN PSYCHOLOGY Sanilevici, M., Reuveni, O., Lev-Ari, S., Golland, Y., Levit-Binnun, N. 2021; 12: 720965


    The COVID-19 pandemic imposed extreme living conditions of social distancing, which triggered negative mental health problems and created challenges in seeking mental health support. Mindfulness-based interventions (MBIs) have been found to enhance wellbeing and mental health by reducing stress and anxiety and improving emotion regulation. Preliminary evidence suggests that online, synchronous MBIs may produce beneficial effects similar to face-to-face programs. However, the effectiveness of such online-MBIs to support mental health in highly stressful times, such as a global pandemic, requires further study. To this end, we investigated the effect of an online 8-week Mindfulness-Based Stress Reduction (MBSR) program on aspects of mental health during the first wave of the COVID-19 pandemic. Participants (N=92) who expressed interest in discounted online-MBSR programs were recruited for the study. The division into experimental and control groups was based on actual enrollment to the courses. Those who enrolled in a program were assigned to the experimental condition and those who decided not to enroll served as controls. Participants were assessed pre-intervention, post-intervention, and 1-month post-intervention for levels of mindfulness, perceived stress, anxiety, emotion regulation, and intolerance of uncertainty. Differences between the groups were tested using the general linear mixed effects model (GLMM) and Individual Growth Curve Models (IGCM) in intent to treat analysis. The findings indicated that, relative to the control group, MBSR improved mindfulness abilities (p <0.001), decreased anxiety (p <0.001), and stress (p <0.001) and increased emotion regulation (p <0.001). These effects were found to persist 1 month after the end of the program, despite the increased governmental public-health restrictions due to COVID-19 at that time. The ability to tolerate uncertainty, a central characteristic of the pandemic, was not found to be affected by the program. A mediation analysis revealed that the effect of the intervention on mental health improvement was partially mediated by the improvement in emotion regulation. Overall, the findings provide positive evidence for the feasibility of an online-MBSR program to support the mental health of individuals from the general population through the mediation of emotion regulation in challenging times, such as a global pandemic.

    View details for DOI 10.3389/fpsyg.2021.720965

    View details for Web of Science ID 000725583900001

    View details for PubMedID 34858260

    View details for PubMedCentralID PMC8631924

  • The Effect of Cognitive Behavioral Group Therapy on Children's Self-Esteem CHILDREN-BASEL Epel, N., Zohar, A., Artom, A., Novak, A., Lev-Ari, S. 2021; 8 (11)


    (1) Background: Self-esteem plays an important role in developing emotional resilience and wellbeing in children. Yet, there has been little related research on Cognitive Behavioral Group Therapy on this topic. Our aims were to assess the effect of the Child Self-Esteem CBT (CSE-CBT) protocol on children's self-esteem in grades five and six; to assess the effect of the CSE-CBT protocol on the therapeutic process; and to explore the feasibility of delivering the CSE-CBT protocol in a school setting. (2) Methods: Eighty elementary school children in grades five and six, divided into four intervention and four control groups, attended 12 structured sessions using the CSE-CBT protocol, led by specially trained teachers. The children completed questionnaires to assess their self-esteem at the beginning and at the end of the study, and answered weekly questionnaires that assessed therapeutic process. Hierarchical linear modeling was used to analyze the data. (3) Results: The CSE-CBT protocol had a significant effect on improving children's self-esteem over the course of the study, regardless of the children's working alliance with the teacher leading the group. (4) Conclusions: The findings suggest that the CSE-CBT protocol has the potential to benefit children's self-esteem and indicate that school teachers can be trained to administer the CBT-protocol.

    View details for DOI 10.3390/children8110958

    View details for Web of Science ID 000724517200001

    View details for PubMedID 34828671

    View details for PubMedCentralID PMC8617969

  • Excess Body Weight and Long-Term Incidence of Lung and Colon Cancer in Men; Follow-Up Study of 43 Years INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH Gepner, Y., Lev-ari, S., Goldbourt, U. 2021; 18 (19)


    Most evidence for an association between excess body weight and cancer risk has been derived from studies of relatively short duration with little reference to the effect on tumor site. This study was designed to evaluate the association between categories of body mass index (BMI: <20, 20-25, 25-30, and >30 kg/m2) and the incidence of colon and lung cancer over 43 years of follow-up (1963-2006), in 10,043 men from the Israeli Ischemic Heart Disease (IIHD) prospective cohort (mean age at baseline 49.3 years, mean BMI 25.7 kg/m2). Data from the Israel National Cancer Registry was linked with the IIHD, and the Cox proportional hazards regression model was applied to analyze the relative risks for lung and colon cancer across BMI categories at baseline. Three hundred cases of lung cancer (2.9%) and 328 cases of colon cancer (3.3%) were diagnosed in the total population. Applying a multivariate model adjusted for age, smoking intensity, and total cholesterol, higher BMI category was associated with an increased risk of colon cancer [HR = 1.22 (95% CI 1.02-1.45)], and with a decreased risk for lung cancer [HR = 0.66 (95% CI 0.56-0.77)]. In this long-term follow-up study over four decades, we observed a consistent dose-response pattern between BMI and increased risk for colon cancer, but decreased risk for lung cancer. Specific associations between excess body weight and cancer risk may suggest different patterns of body fat and cancer incidence at a given site.

    View details for DOI 10.3390/ijerph181910418

    View details for Web of Science ID 000707459600001

    View details for PubMedID 34639717

    View details for PubMedCentralID PMC8508109

  • Predictors of the CD24/CD11b Biomarker among Healthy Subjects JOURNAL OF PERSONALIZED MEDICINE Shapira, S., Aiger, G., Ohayon, A., Kazanov, D., Mdah, F., Shimon, M., Hay-Levy, M., Banon, L., Laskov, I., Mashiah, J., Lev-Ari, S., Arber, N. 2021; 11 (9)


    The CD24 gene has raised considerable interest in tumor biology as a new prognostic factor and a biomarker for the early detection of cancer. There are currently no studies that assess predictors of CD24 in blood tests among healthy individuals. Our aims were (1) to evaluate predictors of the CD24/CD11b biomarker among healthy subjects and (2) to assess CD24/CD11b levels of participants with and without benign tumors. Our cohort included 1640 healthy subjects, aged 20-85, recruited at the Health Promotion and Integrated Cancer Prevention Center (ICPC) in the Tel Aviv Medical Center. Eligible subjects completed a detailed questionnaire on medical history and other epidemiologic information. CD24/CD11b expression in peripheral blood leukocytes (PBLs) obtained from blood samples of participants was analyzed by flow cytometry. Our results showed that the average levels of CD24/CD11b in healthy patients (22.8 ± 9.3) was statistically significant lower compared to subjects with benign cancers (26.1 ± 10.5, p < 0.001). Our multivariable analysis demonstrated that elevated levels of CRP (coefficient β: 1.98, p = 0.011) were significantly associated with high levels of CD24/CD11b expression among healthy participants. Other risk factors of cancer were not associated with elevated CD24 levels among healthy subjects. In conclusion, our findings may assist in further development and optimization of the CD24/CD11b biomarker to serve as a cancer screening test for early detection of cancer among the healthy population.

    View details for DOI 10.3390/jpm11090939

    View details for Web of Science ID 000699513100001

    View details for PubMedID 34575716

    View details for PubMedCentralID PMC8471999

  • Feasibly of CD24/CD11b as a Screening Test for Hematological Malignancies JOURNAL OF PERSONALIZED MEDICINE Shapira, S., Kazanov, D., Mdah, F., Yaakobi, H., Herishanu, Y., Perry, C., Avivi, I., Itchaki, G., Shacham-Abulafia, A., Raanani, P., Hay-Levy, M., Aiger, G., Mashiah, J., Lev-Ari, S., Arber, N. 2021; 11 (8)


    An estimated 1.24 million blood cancer cases occur annually worldwide, accounting for approximately 6% of all cancer cases. Currently, there are no standardized hematology cancer screening tests that are recommended for the general population. CD24 is a mucin-like cell surface molecule and P-selectin ligand, which plays a significant role in the maturation of B-lymphocytes and was found to be overexpressed in a number of hematological malignancies. Our primary aim was to assess the sensitivity and specificity of the CD24/CD11b-based blood test for the detection of hematological malignancies. Our cohort included 488 subjects with positive hematological cancer diagnosis (n = 122) and healthy subjects (n = 366). CD24/CD11b expression in peripheral blood leukocytes (PBLs) obtained from blood samples of participants was analyzed by flow cytometry. Our results demonstrated that the average levels of CD24/CD11b in healthy patients (21.7 ± 9.0) were statistically significantly lower compared to levels of CD24/CD11b in cancer patients (29.5 ± 18.7, p < 0.001). The highest levels of CD24/CD11b were found in multiple myeloma (39.1 ± 23.6), followed by chronic myeloid leukemia (33.0 ± 13.7) and non-Hodgkin lymphoma (32.3 ± 13.3). The test had an overall sensitivity for hematologic cancers of 78.5% (95% CI, 70.7-86.3%) and specificity of 80.2% (95% CI, 76.1-84.3%). In conclusion, our findings indicate the feasibility of a CD24/CD11b-based blood test as a screening test of hematological malignancies.

    View details for DOI 10.3390/jpm11080724

    View details for Web of Science ID 000690508100001

    View details for PubMedID 34442367

    View details for PubMedCentralID PMC8399145

  • Tone it down: Vagal nerve activity is associated with pro-inflammatory and anti-viral factors in breast cancer - An exploratory study COMPREHENSIVE PSYCHONEUROENDOCRINOLOGY Ricon-Becker, I., Fogel, E., Cole, S. W., Haldar, R., Lev-Ari, S., Gidron, Y. 2021; 7: 100057


    In response to adverse social-environmental conditions, leukocytes gene expression profile is altered in a pattern recognized as the conserved transcriptional response to adversity (CTRA). This entails the up-regulated expression of pro-inflammatory genes and down-regulated expression of genes involved in type-I interferon (IFN) related anti-viral immunity. In contrast, vagal nerve activity is recognized as a significant anti-inflammatory modulator. In this work, we investigated the association between CTRA and vagal activity indicated by the standard deviation of all NN interval (SDNN), a measure of heart-rate variability, in breast cancer patients awaiting surgery (n = 16). This association was tested both at the molecular leukocyte transcription factor activity level, as well as at the cytokines serum levels. We found an association between higher SDNN and increased interferon (IFN) related anti-viral pathways, both on the leukocyte transcription factor level and serum protein level. Unexpectedly, we also found a positive correlation between higher SDNN and pro-inflammatory transcription factor activity and cytokine serum level, potentially suggesting that increased vagal activity was induced by increased inflammation, in the context of pre-surgical stress and the presence of malignant tissue. Transcription origin analysis (TOA) suggests a role for monocyte and B-cells in the anti-inflammatory and anti-metastatic effects induced by vagal nerve signaling. Larger prospective studies are needed to verify and elaborate on the results from this small cross-sectional study.

    View details for DOI 10.1016/j.cpnec.2021.100057

    View details for Web of Science ID 001109075100021

    View details for PubMedID 35757058

    View details for PubMedCentralID PMC9216392

  • Health Literacy, Primary Care Health Care Providers, and Communication. Health literacy research and practice Mor-Anavy, S., Lev-Ari, S., Levin-Zamir, D. 2021; 5 (3): e194-e200


    BACKGROUND: Decision-makers and health professionals face challenges in providing quality medical services while optimizing diminishing resources. Health literacy is associated with health outcomes and health system costs and influences the way in which communication is managed in the health system.OBJECTIVE: This study examined the association between the level of health literacy of service providers in the community, their awareness of health literacy, their attitudes toward health literacy promotion, and the way in which they communicate with patients with low health literacy.METHODS: A cross-sectional analytic study was conducted among 50 physicians and 50 administrative staff members in community clinics of the Maccabi Health Maintenance Organization in Israel.KEY RESULTS: Significant positive associations were found (p < .05) between the level of health literacy, the attitudes toward health literacy promotion, and the degree to which special communication techniques were used when treating patients with low health literacy. Significant associations were found (p < .01) between the level of awareness, as well as the attitudes toward health literacy promotion and the degree to which communication techniques were applied. Higher health literacy is associated with more favorable attitudes toward health literacy promotion. Additionally, a significant positive association (p < .01) was found between the attitudes toward health literacy promotion and the use of communication techniques. No mediation was found among the research variables.CONCLUSIONS: To the best of our knowledge, this is the first study that examines health literacy among physicians. The results indicate gaps in the awareness of, and attitudes toward, health literacy among community health care providers, thus suggesting the need for developing and applying guidelines for improving efforts of health system providers regarding health literacy and for applying recommended tools for health communication. [HLRP: Health Literacy Research and Practice. 2021;5(3):e194-e200.] Plain Language Summary: This study examined the link between the health literacy of health care providers (e.g., physicians, service administrators), their awareness and attitudes toward health literacy promotion, and how they communicate with patients with low health literacy. The findings showed significant and positive relationships between these aspects of health literacy as well as gaps in the health care system that need to be addressed.

    View details for DOI 10.3928/24748307-20210529-01

    View details for PubMedID 34260319

  • Rh2-enriched Korean ginseng (Ginseng Rh2+) inhibits tumor growth and development of metastasis of non-small cell lung cancer FOOD & FUNCTION Lev-ari, S., Starr, A. N., Vexler, A., Kalich-Philosoph, L., Yoo, H., Kwon, K., Yadgar, M., Bondar, E., Bar-shai, A., Volovitz, I., Schwarz, Y. 2021; 12 (17): 8068-8077


    While there are multiple studies on the anti-tumoral effects of Panax ginseng as active ingredients (one or more ginsenosides derived from the extract) or as a whole plant extract, there is a lack of studies to assess the effects Panax ginseng's of active ingredients combined with the whole plant extract. Our aim was to study the effect of whole ginseng, enriched in the anti-tumoral Rh2 component and other ginsenosides (Ginseng Rh2+), on the metastatic capacity of non-small cell lung cancer (NSCLC).We evaluated the effects of Ginseng Rh2+ on survival, migration and motility, induction of apoptosis, and expression of its apoptosis-related proteins in non-small cell lung cancer (NSCLC) cells in vitro and on primary tumor growth and metastatic capacity in a syngeneic mouse lung cancer model in vivo. The effects of Ginseng Rh2+ on NSCLC cells were studied in vitro using: a colorimetric tetrazolium salt (XTT) assay, annexin V-FITC/PI, western blotting, wound healing motility assay, Transwell migration and cell adhesion assays. In vivo, mice were inoculated with Lewis mouse lung carcinoma cells subcutaneously to evaluate local tumor growth, or intravenously to evaluate the effects of Ginseng Rh2+ on development of experimental metastases. Mice were treated by intraperitoneal administration of Ginseng Rh2+ (0.005-0.5 g kg-1) on days 6, 10, and 14 after tumor injection.We found that Ginseng Rh2+ increased the apoptosis of NSCLC cells in vitro, demonstrating dose dependent down-regulation of the Bcl-2 anti-apoptotic gene and concurrent up-regulation of the Bax pro-apoptotic gene. Ginseng Rh2+ inhibited the tumor cells' capacity to attach to the ECM-related matrix and reduced cell migration. In vivo, Ginseng Rh2+ inhibited local tumor growth and reduced the development of experimental lung metastases.Our study suggests that Ginseng Rh2+ may potentially be used as a therapeutic agent for treatment of NSCLC.

    View details for DOI 10.1039/d1fo00643f

    View details for Web of Science ID 000674763400001

    View details for PubMedID 34286798

  • Immune Responses to SARS-CoV2 Mirror Societal Responses to COVID-19: Identifying Factors Underlying a Successful Viral Response BIOLOGY-BASEL Lev-Ari, S., Rolnik, B., Volovitz, I. 2021; 10 (6)


    The adaptive immune system was sculpted to protect individuals, societies, and species since its inception, developing effective strategies to cope with emerging pathogens. Here, we show that similar successful or failed dynamics govern personal and societal responses to a pathogen as SARS-CoV2. Understanding the self-similarity between the health-protective measures taken to protect the individual or the society, help identify critical factors underlying the effectiveness of societal response to a pathogenic challenge. These include (1) the quick employment of adaptive-like, pathogen-specific strategies to cope with the threat including the development of "memory-like responses"; (2) enabling productive coaction and interaction within the society by employing effective decision-making processes; and (3) the quick inhibition of positive feedback loops generated by hazardous or false information. Learning from adaptive anti-pathogen immune responses, policymakers and scientists could reduce the direct damages associated with COVID-19 and avert an avoidable "social cytokine storm" with its ensuing socioeconomic damage.

    View details for DOI 10.3390/biology10060485

    View details for Web of Science ID 000666948100001

    View details for PubMedID 34072585

    View details for PubMedCentralID PMC8228441

  • Inquiry Based Stress Reduction (IBSR) Improves Overall Stuttering Experience among Adults Who Stutter: A Randomized Controlled Trial. Journal of clinical medicine Feldman, O., Goldstien, E., Rolnik, B., Ganz, A. B., Lev-Ari, S. 2021; 10 (10)


    Stuttering is a speech disorder that can cause disturbances in the timing and flow of speech. In addition to being a communication disorder, stuttering is often accompanied by a reduction in the quality of life and has impacts on social status, mental well-being, self-acceptance, and the chances of integration into the labor market. The Inquiry Based Stress Reduction (IBSR) program, developed in the United States by Byron Katie in 1986, is the clinical application of "The Work" method ( and represents an emerging mindfulness and cognitive-reframing method. IBSR has been demonstrated to improve mental health and well-being in adults and may alleviate psychological and psychosocial symptoms of stuttering. The purpose of this trial was to examine the effect of a 12-week IBSR intervention on the overall stuttering experience and indicators of anxiety, psychological flexibility, and well-being among adults who stutter (AWS). This study was a randomized controlled clinical trial. Participants were randomized to IBSR (n = 28) and control (n = 28) groups. Validated questionnaires of overall stuttering experience (OASES-A), anxiety (STAI), psychological flexibility (PFQ), and satisfaction with life (SWLS) were completed before, after, and one month after the intervention. An intention-to-treat approach was implemented for analysis. Our results show that participants in the IBSR intervention group exhibited a greater improvement in their overall stuttering experience as compared to the control group, as well as in general information on stuttering awareness and perception, reactions to stuttering, communication in daily situations, and quality of life. In addition, we found a greater reduction in anxiety levels and an increase in satisfaction-with-life scores in the IBSR group. These results indicate that IBSR can improve the overall stuttering experience.

    View details for DOI 10.3390/jcm10102187

    View details for PubMedID 34070161

    View details for PubMedCentralID PMC8158472

  • Inquiry Based Stress Reduction (IBSR) Improves Overall Stuttering Experience among Adults Who Stutter: A Randomized Controlled Trial JOURNAL OF CLINICAL MEDICINE Feldman, O., Goldstien, E., Rolnik, B., Ganz, A. B., Lev-Ari, S. 2021; 10 (10)
  • Effect of Inquiry-Based Stress Reduction (IBSR) Intervention on Well-Being, Resilience and Burnout of Teachers during the COVID-19 Pandemic. International journal of environmental research and public health Zadok-Gurman, T., Jakobovich, R., Dvash, E., Zafrani, K., Rolnik, B., Ganz, A. B., Lev-Ari, S. 2021; 18 (7)


    Objective: The COVID-19 pandemic has had a major impact on teachers professional and personal lives. Our primary aim was to assess the effect of a blended Inquiry-Based Stress Reduction (IBSR), an emerging mindfulness and cognitive reframing intervention on teacher's well-being. Our secondary aims were to assess the effect of IBSR on resilience, burnout, mindfulness, and stress among teachers during the COVID-19 pandemic. Methods: The study was a prospective controlled trial with an intervention group (N = 35) and a comparison control group (N = 32). The intervention took place in the Jerusalem District throughout the school year from November 2019 to May 2020. The sessions were conducted in blended learning that included traditional learning (face-to-face) and online learning. Data was analyzed on an intention-to-treat basis. Results: IBSR blended intervention enhanced the resilience and improved the subjective and psychological well-being of teachers in spite of the breakout of the COVID-19 pandemic and the first lockdown in Israel. Simultaneously the control group suffered from enhanced burnout levels and a decline in psychological and subjective well-being. Conclusions: Implementation of IBSR blended intervention during the school year may benefit teachers' well-being and ability to flourish, even during stressful events such as the COVID-19 pandemic.

    View details for DOI 10.3390/ijerph18073689

    View details for PubMedID 33916258

  • Dissatisfaction with Married Life in Men Is Related to Increased Stroke and All-Cause Mortality JOURNAL OF CLINICAL MEDICINE Lev-ari, S., Gepner, Y., Goldbourt, U. 2021; 10 (8)


    The objectives of this study were to assess the association between marital satisfaction and specific and all-cause mortality, and to examine whether this association is independent of other known risk factors for early mortality. In this prospective cohort, male Israeli civil servants and municipal employees (n = 8945) underwent an extensive appraisal of health and behavioral patterns and were followed for more than three decades. Cox proportional hazards analysis was used to estimate the relative risks for stroke and all-cause mortality over time across marital satisfaction categories. During the 32 years of follow-up, 5736 (64.1%) died. Dissatisfaction with married life was related to increased long-term risk of stroke (HR = 1.94; 95%CI, 1.41-2.90) and all-cause mortality (HR = 1.21; 95%CI, 1.04-1.41). The latter association was of a similar order of magnitude to other known risk factors for early mortality, such as people with a history of smoking (HR = 1.37; 95%CI, 1.30-1.48) compared to people who have never smoked and for physically inactive participants (HR = 1.21; 95%CI, 1.14-1.37) compared to physically active participants. The results of our study suggest that marital dissatisfaction may predict an elevated risk of all-cause mortality. Assessing marital satisfaction and measuring the health benefits of marital education programs for couples should be implemented as part of health promotion strategies for the general population.

    View details for DOI 10.3390/jcm10081729

    View details for Web of Science ID 000644473100001

    View details for PubMedID 33923661

    View details for PubMedCentralID PMC8073503

  • Continued Participation of Israeli Adolescents in Online Sports Programs during the COVID-19 Pandemic Is Associated with Higher Resilience INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH Constantini, K., Markus, I., Epel, N., Jakobovich, R., Gepner, Y., Lev-Ari, S. 2021; 18 (8)


    Background: Coronavirus disease 2019 (COVID-19) has forced adolescents to adapt rapidly to a new reality of physical and social distancing, while introducing a range of new sources of stress and adversity. Our primary aim was to study the relationship between adolescents' resilience and their participation in online sports programs during the COVID-19 pandemic lockdown period. Our secondary aims were to assess the associations between the organized sports programs' determinants and resilience. Methods: Online surveys designed to examine resilience, lifestyle, psychosocial health and characteristics of the organized sports programs were administered to 473 adolescents who were enrolled in organized sports programs before the COVID-19 pandemic. Results: Adolescents who continued to participate in online structured programs during the lockdown period were significantly more resilient and physically active, had higher self-related health, satisfaction with life, and ability to cope during the pandemic, compared to those who did not participate. Relationships with the adult instructor and levels of physical activity were the most important factors of the programs that were associated with resilience. Conclusions: Participation of adolescents in sports programs is an important resource associated with higher levels of resilience. Youth programs should continue their activities during globally challenging times, such as the COVID-19 pandemic.

    View details for DOI 10.3390/ijerph18084386

    View details for Web of Science ID 000644117200001

    View details for PubMedID 33924245

    View details for PubMedCentralID PMC8074771

  • Health promotion preparedness for health crises - a 'must' or 'nice to have'? Case studies and global lessons learned from the COVID-19 Pandemic GLOBAL HEALTH PROMOTION Levin-Zamir, D., Sorensen, K., Su, T., Sentell, T., Rowlands, G., Messer, M., Pleasant, A., Nunes, L., Lev-Ari, S., Okan, O. 2021; 28 (2): 27-37


    The current COVID-19 pandemic has exposed missing links between health promotion and national/global health emergency policies. In response, health promotion initiatives were urgently developed and applied around the world. A selection of case studies from five countries, based on the Socio-Ecological Model of Health Promotion, exemplify 'real-world' action and challenges for health promotion intervention, research, and policy during the COVID-19 pandemic. Interventions range from a focus on individuals/families, organizations, communities and in healthcare, public health, education and media systems, health-promoting settings, and policy. Lessons learned highlight the need for emphasizing equity, trust, systems approach, and sustained action in future health promotion preparedness strategies. Challenges and opportunities are highlighted regarding the need for rapid response, clear communication based on health literacy, and collaboration across countries, disciplines, and health and education systems for meaningful solutions to global health crises.

    View details for DOI 10.1177/1757975921998639

    View details for Web of Science ID 000634474600001

    View details for PubMedID 33775167

    View details for PubMedCentralID PMC8246413

  • Adequacy of Web-Based Activities as a Substitute for In-Person Activities for Older Persons During the COVID-19 Pandemic: Survey Study (vol 23, e25848, 2021) JOURNAL OF MEDICAL INTERNET RESEARCH Cohen-Mansfield, J., Muff, A., Meschiany, G., Lev-Ari, S. 2021; 23 (2): e27687


    [This corrects the article DOI: 10.2196/25848.].

    View details for DOI 10.2196/27687

    View details for Web of Science ID 000618528500008

    View details for PubMedID 33591925

    View details for PubMedCentralID PMC7925141

  • Adequacy of Web-Based Activities as a Substitute for In-Person Activities for Older Persons During the COVID-19 Pandemic: Survey Study JOURNAL OF MEDICAL INTERNET RESEARCH Cohen-Mansfield, J., Muff, A., Meschiany, G., Lev-Ari, S. 2021; 23 (1): e25848


    Senior centers and other types of clubs provide activities for older adults to address boredom, social isolation, and loneliness. Due to the COVID-19 pandemic, most of these activities have been cancelled. A limited range of web-based activities have been offered as alternatives. However, the effectiveness of these web-based group activities for older adults has scarcely been researched.We aimed to understand the extent to which web-based activities for older adults provide an adequate substitute for in-person activities.In this telephone survey, we interviewed 105 older adults in Israel who had been offered the opportunity to participate in web-based activities after routine activities closed due to the COVID-19 pandemic. Of the total sample, 49/105 (46.7%) participated in the activities and 56/105 (53.3%) did not. We inquired about the respondents' background characteristics, satisfaction with the activities, and reasons for participation or nonparticipation.The respondents who participated in the web-based activities tended to be highly satisfied with at least some of them. They rated the enjoyment derived from the content of the activity as the most important motivator, followed by maintaining a routine and by enjoying the group and the presence of others. Over 50% of the participants (28/49, 57%) wished to continue with the exercise programming after the end of the COVID-19 pandemic, and 41% (20/49) wished to continue with the web-based lectures. Participants were more likely to report partaking in alternative activities than nonparticipants (P=.04). The most common reasons cited by nonparticipants were being unaware of the web-based program (24/56, 43%) despite a notification having been sent to the entire sample, lack of interest in the content (18/56, 32%), and technical issues (13/56, 23%), such as not owning or being able to fully use a computer. Both participants and nonparticipants were interested in a wide range of topics, with many being very particular about the topics they wished to access. Approximately half expressed willingness to pay for access; those who were willing to pay tended to have more years of education (P=.03).Our findings suggest a need for web-based activities for countering boredom and feelings of isolation. The main factors that influence the use, efficacy, and sustainability of online activities are access, motivational and need-fulfilling factors, and whether the activities are sufficiently tailored to individuals' preferences and abilities. Challenges in substituting in-person services are promoting social relationships that are currently not sufficiently incorporated into most web-based programs, accommodating a wider range of topics, and increasing the accessibility of current programs to older adults, especially those who are homebound, both during and after the COVID-19 pandemic.

    View details for DOI 10.2196/25848

    View details for Web of Science ID 000610775300007

    View details for PubMedID 33439851

    View details for PubMedCentralID PMC7836908

  • The Effect of Inquiry-Based Stress Reduction on Teacher Burnout: A Controlled Trial. Brain sciences Schnaider-Levi, L., Ganz, A. B., Zafrani, K., Goldman, Z., Mitnik, I., Rolnik, B., Lev-Ari, S. 2020; 10 (7)


    Burnout is a well-known phenomenon with significant social, biological and economic costs. In particular, teacher burnout is associated with unfavorable mental health outcomes and economic costs due to reduced hours and teacher turnover. This study investigated the effect of an Inquiry-Based Stress Reduction (IBSR) cognitive-reframing program on teacher burnout using a quasi-experimental design. Fifty-three teachers participated in a prospective intervention with a passive control group. The intervention group completed a 12-week IBSR program with 4.5 h of weekly engagement. Relative to control, teachers in the intervention group showed greater improvements in emotional exhaustion (18.8 ± 5.2 to 15.9 ± 5.7 vs. 16.0 ± 4.8 to 17.4 ± 4.8; p = 0.01) and personal accomplishment (21.8 ± 5.0 to 24.6 ± 4.3 vs. 21.9 ± 4.5 to 22.8 ± 4.3; p = 0.04). Significant correlations were found between change in emotional exhaustion and negative affect (positive correlation; r = 0.32; p = 0.034) and between personal accomplishment and perceived stress (negative correlation; r = -0.451; p = 0.002). This study demonstrates the potential of IBSR to improve teacher well-being. Future randomized studies are needed to evaluate the causality of IBSR in reducing burnout among teachers and other high-stress workplaces.

    View details for DOI 10.3390/brainsci10070468

    View details for PubMedID 32708055

  • Combined Effect of Moringa oleifera and Ionizing Radiation on Survival and Metastatic Activity of Pancreatic Cancer Cells INTEGRATIVE CANCER THERAPIES Hagoel, L., Vexler, A., Kalich-Philosoph, L., Earon, G., Ron, I., Shtabsky, A., Marmor, S., Lev-Ari, S. 2019; 18: 1534735419828829


    Radiotherapy is one of the main treatments for malignancies. Radioresistance is a major obstacle in this treatment, calling for new treatments to improve radiotherapy outcome. Herbal medicine has low toxicity and could be a source for new radio-enhancing agents. Moringa oleifera (moringa) is a well-known medicinal plant with antiproliferative and antimetastatic properties. Possible mechanisms of moringa anticancer activity may be related to the expression of PARP-1, Bcl-2, COX-2, p65, p-IκB-a, and others.The aims of the present study were to investigate effect of moringa alone and combined with radiation on survival and metastatic activity of pancreatic cancer cells and on tumor growth.The combination of moringa and radiation significantly inhibited PANC-1 cell survival in a dose-dependent manner, as tested by clonogenic and XTT assays. Moreover, standard transwell cell migration/invasion assays demonstrated reduced metastatic activity of these cells. Pyruvate mitigated the inhibitory effect of combined treatment on cell survival. Flow cytometry of moringa-treated cells revealed induction of apoptosis. Western blot analysis found that the combined treatment decreased expression of the pro-apoptotic protein Bcl-2, and downregulated the key component of DNA repair pathways PARP-1 and the NF-κB-related proteins IκB-α, p65-subunit, and COX-2. Moringa significantly inhibited growth of subcutaneous tumors generated by PANC-1 cells in nude mice. Immunohistochemical analysis demonstrated moringa's antiproliferative and antiangiogenic effects.Moringa decreased pancreatic cancer cell survival and metastatic activity and significantly inhibited tumor growth. The combination of moringa plus radiation resulted in an additional inhibitory effect that provided the rationale for further investigation of this combination as a novel strategy to overcome pancreatic cancer cell radioresistance.

    View details for DOI 10.1177/1534735419828829

    View details for Web of Science ID 000461166100001

    View details for PubMedID 30862207

    View details for PubMedCentralID PMC6416749

  • The effects of Inquiry-Based Stress Reduction (IBSR) on mental health and well-being among a non-clinical sample COMPLEMENTARY THERAPIES IN CLINICAL PRACTICE Smernoff, E., Mitnik, I., Lev-ari, S. 2019; 34: 30-34


    Mental problems are highly common among the general population. Mind-body interventions were found to be highly effective in treating them. The current study assessed the effect of Inquiry-Based Stress Reduction (IBSR) meditation on psychological parameters in a general population sample.Ninety-seven Participants enrolled in a 28-day workshop and completed a set of self-administered measures before and after the workshop. Outcome measures included Beck Depression Inventory-II (BDI-II), Quick Inventory of Depressive Symptomology-Self Report (QIDS-SR16), Outcome Questionnaire OQ-45.2, The Quality of Life Inventory (QOLI), State-Trait Anxiety Inventory Form (STAI), State-Trait Anger Expression Inventory (STAXI) (State), Subjective Happiness Scale (SHS), Eating Attitudes Test (EAT).BDI scale decreased significantly before and after the intervention. QIDS scale improved significantly from T1 to T2 (p < 0.001). Outcome questionnaire decreased significantly at T2. Quality of life scores improved significantly between T1 and T2 (p < 0.001). Anxiety state and trait scores decreased significantly after the intervention (p < 0.001) All the subscales of anger decreased significantly after the intervention (p < 0.001).Subjective happiness improved significantly (p < 0.001).IBSR meditation improved various psychological scales among a general population sample. Further controlled studies should evaluate the clinical implementation of IBSR among the general population.

    View details for DOI 10.1016/j.ctcp.2018.10.015

    View details for Web of Science ID 000457640000006

    View details for PubMedID 30712742

  • Modified Citrus Pectin as a Potential Sensitizer for Radiotherapy in Prostate Cancer INTEGRATIVE CANCER THERAPIES Conti, S., Vexler, A., Hagoel, L., Kalich-Philosoph, L., Corn, B. W., Honig, N., Shtraus, N., Meir, Y., Ron, I., Eliaz, I., Lev-Ari, S. 2018; 17 (4): 1225-1234


    Radiotherapy is one of the primary therapies for localized prostatic carcinoma. Therefore, there is an emerging need to sensitize prostatic cancer cells to chemotherapy/radiotherapy. Modified citrus pectin (MCP) is an effective inhibitor of galectin-3 (Gal-3), which is correlated with tumor progression, proliferation, angiogenesis, and apoptosis.This study was directed to evaluate the efficacy of combining ionizing radiation (IR) with MCP on PCa cells.Effects of treatments on PCa cells survival were evaluated using XTT assay, flow cytometry, and clonogenic survival assay. Expression of selected proteins was estimated using western blotting. Cell motility, migration, and invasion were determined. Contribution of reactive oxygen species production to treatment effects on cell viability was tested.Radiotherapy combined with MCP reduced viability and enhanced radiosensitivity associated with a decrease in Gal-3, cleavage of the precursor of caspase-3, increased expression of the pro-apoptotic protein Bax, and downregulation of DNA repair pathways, poly-ADP-ribose polymerase, and proliferating cell nuclear antigen. MCP significantly reduced the invasive and migratory potential of PCa cells. Combining sodium pyruvate with MCP and IR mitigated the effect on cell viability.Our findings demonstrated that MCP sensitized PCa cells to IR by downregulating anti-apoptotic Gal-3, modulating DNA repair pathways, and increasing ROS production. For the first time the correlation between MCP, radiotherapy, and Gal-3 for prostatic cancer treatment was found. In addition, MCP reduced the metastatic properties of PCa cells. These findings provide MCP as a radiosensitizing agent to enhance IR cytotoxicity, overcome radioresistance, and reduce clinical IR dose.

    View details for DOI 10.1177/1534735418790382

    View details for Web of Science ID 000450322400025

    View details for PubMedID 30043669

    View details for PubMedCentralID PMC6247563

  • Combined acetyl-11-keto-β-boswellic acid and radiation treatment inhibited glioblastoma tumor cells PLOS ONE Conti, S., Vexler, A., Edry-Botzer, L., Kalich-Philosoph, L., Corn, B. W., Shtraus, N., Meir, Y., Hagoel, L., Shtabsky, A., Marmor, S., Earon, G., Lev-Ari, S. 2018; 13 (7): e0198627


    Glioblastoma multiforme (GBM) is the most common and most aggressive subtype of malignant gliomas. The current standard of care for newly diagnosed GBM patients involves maximal surgical debulking, followed by radiation therapy and temozolomide chemotherapy. Despite the advances in GBM therapy, its outcome remains poor with a median survival of less than two years. This poor outcome is partly due to the ability of GBM tumors to acquire adaptive resistance to therapy and in particular to radiation. One of the mechanisms contributing to GBM tumor progression and resistance is an aberrant activation of NF-ĸB, a family of inducible transcription factors that play a pivotal role in regulation of many immune, inflammatory and carcinogenic responses. Acetyl-11-keto-β-boswellic acid (AKBA) is a pentacyclic terpenoid extracted from the gum Ayurvedic therapeutic plant Boswellia serrata. AKBA is anti-inflammatory agent that exhibits potent cytotoxic activities against various types of tumors including GBM. One of the mechanisms underlying AKBA anti-tumor activity is its ability to modulate the NF-ĸB signaling pathway. The present study investigated in vitro and in vivo the effect of combining AKBA with ionizing radiation in the treatment of GBM and assessed AKBA anti-tumor activity and radio-enhancing potential. The effect of AKBA and/or radiation on the survival of cultured glioblastoma cancer cells was evaluated by XTT assay. The mode of interaction of treatments tested was calculated using CalcuSyn software. Inducing of apoptosis following AKBA treatment was evaluated using flow cytometry. The effect of combined treatment on the expression of PARP protein was analysed by Western blot assay. Ectopic (subcutaneous) GBM model in nude mice was used for the evaluation of the effect of combined treatment on tumor growth. Immunohistochemical analysis of formalin-fixed paraffin-embedded tumor sections was used to assess treatment-related changes in Ki-67, CD31, p53, Bcl-2 and NF-ĸB-inhibitor IĸB-α. AKBA treatment was found to inhibit the survival of all four tested cell lines in a dose dependent manner. The combined treatment resulted in a more significant inhibitory effect compared to the effect of treatment with radiation alone. A synergistic effect was detected in some of the tested cell lines. Flow cytometric analysis with Annexin V-FITC/PI double staining of AKBA treated cells indicated induction of apoptosis. AKBA apoptotic activity was also confirmed by PARP cleavage detected by Western blot analysis. The combined treatment suppressed tumor growth in vivo compared to no treatment and each treatment alone. Immunohistochemical analysis showed anti-angiogenic and anti-proliferative activity of AKBA in vivo. It also demonstrated a decrease in p53 nuclear staining and in Bcl-2 staining and an increase in IĸB-α staining following AKBA treatment both alone and in combination with radiotherapy. In this study, we demonstrated that AKBA exerts potent anti-proliferative and apoptotic activity, and significantly inhibits both the survival of glioblastoma cells in vitro and the growth of tumors generated by these cells. Combination of AKBA with radiotherapy was found to inhibit factors which involved in cell death regulation, tumor progression and radioresistence, therefore it may serve as a novel approach for GBM patients.

    View details for DOI 10.1371/journal.pone.0198627

    View details for Web of Science ID 000437246700004

    View details for PubMedID 29969452

    View details for PubMedCentralID PMC6029770

  • Acupuncture and Reflexology for Chemotherapy-Induced Peripheral Neuropathy in Breast Cancer INTEGRATIVE CANCER THERAPIES Ben-Horin, I., Kahan, P., Ryvo, L., Inbar, M., Lev-Ari, S., Geva, R. 2017; 16 (3): 258-262


    Treatment of chemotherapy-induced peripheral neuropathy (CIPN), which affects approximately 30% to 40% of patients treated with neuropathy-causing agents, is mainly symptomatic. Currently available interventions are of little benefit.This study was conducted as a retrospective analysis of the efficacy of acupuncture and reflexology in alleviating CIPN in breast cancer patients.Medical records of 30 consecutive breast cancer patients who received both chemotherapy and treatment for CIPN according to our Acupuncture and Reflexology Treatment for Neuropathy (ART-N) protocol between 2011 and 2012 were reviewed. Symptom severity was rated at baseline, during, and after treatment.The records of 30 breast cancer patients who had been concomitantly treated with chemotherapy and ART-N for CIPN were retrieved. Two records were incomplete, leaving a total of 28 patients who were enrolled into the study. Twenty patients (71%) had sensory neuropathy, 7 (25%) had motor neuropathy, and 1 (4%) had both sensory and motor neuropathy. Only 2 (10%) of the 20 patients with grades 1 to 2 neuropathy still reported symptoms at 12 months since starting the ART-N protocol. All 8 patients who presented with grades 3 to 4 neuropathy were symptom-free at the 12-month evaluation. Overall, 26 patients (93%) had complete resolution of CIPN symptoms.The results of this study demonstrated that a joint protocol of acupuncture and reflexology has a potential to improve symptoms of CIPN in breast cancer patients. The protocol should be validated on a larger cohort with a control group. It also warrants testing as a preventive intervention.

    View details for DOI 10.1177/1534735417690254

    View details for Web of Science ID 000407929900002

    View details for PubMedID 28150504

    View details for PubMedCentralID PMC5759933

  • Attitudes Among Nurses Toward the Integration of Complementary Medicine Into Supportive Cancer Care ONCOLOGY NURSING FORUM Ben-Arye, E., Shulman, B., Eilon, Y., Woitiz, R., Cherniak, V., Sharabi, I., Sher, O., Reches, H., Katz, Y., Arad, M., Schiff, E., Samuels, N., Caspi, O., Lev-Ari, S., Frenkel, M., Agbarya, A., Admi, H. 2017; 44 (4): 428-434


    To explore the attitudes of nurses treating patients with cancer regarding the use of complementary and integrative medicine (CIM) therapies to reduce symptoms and improve quality of life (QOL). .Prospective and descriptive. .12 hospital and community care settings in Israel. .973 nurses working in oncology and non-oncology departments..A 26-item questionnaire was administered to a convenience sample of nurses treating patients with cancer. .Interest in CIM integration and training in supportive cancer care..Of the 973 nurses who completed the questionnaire, 934 expressed interest in integrating CIM into supportive cancer care. A logistic regression model indicated that nurses with a greater interest in integration tended to be older, believed that CIM improved patients' QOL, and had no structured postgraduate oncology training. Nurses who believed CIM to be beneficial for QOL-related outcomes were more likely to express interest in related training. The goals of such training include improving QOL-related outcomes, such as anxiety, insomnia, gastrointestinal symptoms, and pain. .Most nurses working with patients with cancer are interested in the integration of CIM into supportive cancer care. .Most nurses would like to undergo training in CIM to supplement conventional care. CIM-trained integrative nurses can help promote the integration of patient-centered CIM therapies in supportive cancer care settings.

    View details for DOI 10.1188/17.ONF.428-434

    View details for Web of Science ID 000426406400005

    View details for PubMedID 28632238

  • Inquiry-Based Stress Reduction Meditation Technique for Teacher Burnout:A Qualitative Study MIND BRAIN AND EDUCATION Schnaider-Levi, L., Mitnik, I., Zafrani, K., Goldman, Z., Lev-Ari, S. 2017; 11 (2): 75-84

    View details for DOI 10.1111/mbe.12137

    View details for Web of Science ID 000400813500004

  • Inquiry-based stress reduction (IBSR) meditation technique for <i>BRCA1/2</i> mutation carriers-A qualitative study EUROPEAN JOURNAL OF INTEGRATIVE MEDICINE Landau, C., Mitnik, I., Cohen-Mansfield, J., Tillinger, E., Friedman, E., Lev-Ari, S. 2016; 8 (6): 958-964
  • Randomized controlled trial of Inquiry-Based Stress Reduction (IBSR) technique for <i>BRCA1</i>/<i>2</i> mutation carriers PSYCHO-ONCOLOGY Landau, C., Lev-Ari, S., Cohen-Mansfield, J., Tillinger, E., Geva, R., Tarrasch, R., Mitnik, I., Friedman, E. 2015; 24 (6): 726-731

    View details for DOI 10.1002/pon.3703

    View details for Web of Science ID 000355958000015

    View details for PubMedID 25328041



    "The Work" is a meditative technique that enables the identification and investigation of thoughts that cause an individual stress and suffering. Its core is comprised of four questions and turnarounds that enable the participant to experience a different interpretation of reality. We assessed the effect of "The Work" meditation on quality of life and psychological symptoms in a non-clinical sample.This study was designed as a single-group pilot clinical trial (open label). Participants (n = 197) enrolled in a nine-day training course ("The School for The Work") and completed a set of self-administered measures on three occasions: before the course (n = 197), after the course (n = 164), and six months after course completion (n = 102).Beck Depression Inventory-II (BDI-II), Subjective Happiness Scale (SHS), Quality of Life Inventory (QOLI), Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16), Outcome Questionnaire 45.2 (OQ-45.2), State-Trait Anger Expression Inventory-2 (STAXI-2), and State-Trait Anxiety Inventory (STAI).A mixed models analysis revealed significant positive changes between baseline compared to the end of the intervention and six-month follow-up in all measures: BDI-II (t = 10.24, P < .0001), SHS (t = -9.07, P <.0001), QOLI (t = -5.69, P < .0001), QIDS-SR16 (t = 9.35, P < .0001), OQ-45.2 (t = 11.74, P < .0001), STAXI-2 (State) (t = 3.69, P = .0003), STAXI-2 (Trait) (t = 7.8, P < .0001), STAI (State) (t = 11.46, P < .0001), and STAI (Trait) (t = 10.75, P < .0001).The promising results of this pilot study warrant randomized clinical trials to validate "The Work" meditation technique as an effective intervention for improvement in psychological state and quality of life in the general population.

    View details for DOI 10.1016/j.explore.2014.10.003

    View details for Web of Science ID 000348635900009

    View details for PubMedID 25497228

  • Curcumin induces apoptosis and inhibits growth of orthotopic human non-small cell lung cancer xenografts JOURNAL OF NUTRITIONAL BIOCHEMISTRY Lev-Ari, S., Starr, A., Katzburg, S., Berkovich, L., Rimmon, A., Ben-Yosef, R., Vexler, A., Ron, I., Earon, G. 2014; 25 (8): 843-850


    Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality. Curcumin is involved in various biological pathways leading to inhibition of NSCLC growth. The purpose of this study was to evaluate the effect of curcumin on expression of nuclear factor κB-related proteins in vitro and in vivo and on growth and metastasis in an intralung tumor mouse model. H1975 NSCLC cells were treated with curcumin (0-50 μM) alone, or combined with gemcitabine or cisplatin. The effects of curcumin were evaluated in cell cultures and in vivo, using ectopic and orthotopic lung tumor mouse models. Twenty mice were randomly selected into two equal groups, one that received AIN-076 control diet and one that received the same food but with the addition of 0.6% curcumin 14 days prior to cell implantation and until the end of the experiment. To generate orthotopic tumor, lung cancer cells in Matrigel were injected percutaneously into the left lung of CD-1 nude mice. Western blot analysis showed that the expressions of IkB, nuclear p65, cyclooxygenase 2 (COX-2) and p-ERK1/2 were down-regulated by curcumin in vitro. Curcumin potentiated the gemcitabine- or cisplatin-mediated antitumor effects. Curcumin reduced COX-2 expression in subcutaneous tumors in vivo and caused a 36% decrease in weight of intralung tumors (P=.048) accompanied by a significant survival rate increase (hazard ratio=2.728, P=.036). Curcumin inhibition of COX-2, p65 expression and ERK1/2 activity in NSCLC cells was associated with decreased survival and increased induction of apoptosis. Curcumin significantly reduced tumor growth of orthotopic human NSCLC xenografts and increased survival of treated athymic mice. To evaluate the role of curcumin in chemoprevention and treatment of NSCLC, further clinical trials are required.

    View details for DOI 10.1016/j.jnutbio.2014.03.014

    View details for Web of Science ID 000339455800004

    View details for PubMedID 24835302

  • A prospective pilot clinical trial of "The work" meditation technique for survivors of breast cancer EUROPEAN JOURNAL OF INTEGRATIVE MEDICINE Lev-ari, S., Zilcha-Mano, S., Rivo, L., Geva, R., Ron, I. 2013; 5 (6): 487-494
  • Targeting ErbB-1 and ErbB-4 in irradiated head and neck cancer: Results of in vitro and in vivo studies HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Barnea, I., Haif, S., Keshet, R., Karaush, V., Lev-Ari, S., Khafif, A., Shtabsky, A., Yarden, Y., Vexler, A., Ben Yosef, R. 2013; 35 (3): 399-407


    ErbB oncogenes have a major role in cancer. The role of ErbB-4 in cancer cell biology and the effect of anti-ErbB-1 and anti-ErbB-4 monoclonal antibodies were evaluated in this study.ErbB-4 expression and binding was evaluated by Western blot, enzyme-linked immunosorbent assay (ELISA), fluorescent microscopy, and flow cytometry. Cell survival was measured by XTT assay. Tumor progression was followed up in nude mice model.High ErbB-1 levels in head and neck cancer cell lines were determined, whereas ErbB-4 expression varied. Specific antibody binding to the cells was demonstrated. High ErbB-4 expressing squamous cell carcinoma 1 (SCC-1) cells proliferated faster and generated faster growing tumors in mice. Cetuximab and mAb-3 reduced cell survival proportional to ErbB-1 and ErbB-4 expression. Combination of antibodies with irradiation was most effective in reducing cell survival and tumor growth.ErbB-4 plays a role in head and neck cancer cell biology. Anti-ErbB-4 targeted therapy can serve as a new strategy against head and neck cancer when combined with established treatments.

    View details for DOI 10.1002/hed.22967

    View details for Web of Science ID 000314997800021

    View details for PubMedID 22367849

  • Medical residents' perceptions of their competencies and training needs in health care management: an international comparison BMC MEDICAL EDUCATION Berkenbosch, L., Schoenmaker, S., Ahern, S., Sojnaes, C., Snell, L., Scherpbier, A. A., Busari, J. O. 2013; 13: 212


    Fewer than 6% patients with adenocarcinoma of the pancreas live up to five years after diagnosis. Chemotherapy is currently the standard treatment, however, these tumors often develop drug resistance over time. Agents for increasing the cytotoxic effects of chemotherapy or reducing the cancer cells' chemo-resistance to the drugs are required to improve treatment outcome. Nuclear factor kappa B (NF-kB), a pro-inflammatory transcription factor, reportedly plays a significant role in the resistance of pancreatic cancer cells to apoptosis-based chemotherapy. This study investigated the effect of aqueous Moringa Oleifera leaf extract on cultured human pancreatic cancer cells - Panc-1, p34, and COLO 357, and whether it can potentiates the effect of cisplatin chemotherapy on these cells.The effect of Moringa Oleifera leaf extract alone and in combination with cisplatin on the survival of cultured human pancreatic cancer cells was evaluated by XTT-based colorimetric assay. The distribution of Panc-1 cells in the cell cycle following treatment with Moringa leaf extract was evaluated by flow cytometry, and evaluations of protein levels were via immunoblotting. Data of cell survival following combined treatments were analyzed with Calcusyn software.Moringa Oleifera leaf extract inhibited the growth of all pancreatic cell lines tested. This effect was significant in all cells following exposure to ≥0.75 mg/ml of the extract. Exposure of Panc-1 cells to Moringa leaf extract induced an elevation in the sub-G1 cell population of the cell-cycle, and reduced the expression of p65, p-IkBα and IkBα proteins in crude cell extracts. Lastly, Moringa Oleifera leaf extract synergistically enhanced the cytotoxic effect of cisplatin on Panc-1 cells.Moringa Oleifera leaf extract inhibits the growth of pancreatic cancer cells, the cells NF-κB signaling pathway, and increases the efficacy of chemotherapy in human pancreatic cancer cells.

    View details for DOI 10.1186/1472-6920-13-25

    View details for Web of Science ID 000315774800001

    View details for PubMedID 23957955

    View details for PubMedCentralID PMC3765468

  • Escin Chemosensitizes Human Pancreatic Cancer Cells and Inhibits the Nuclear Factor-kappaB Signaling Pathway BIOCHEMISTRY RESEARCH INTERNATIONAL Rimmon, A., Vexler, A., Berkovich, L., Earon, G., Ron, I., Lev-Ari, S. 2013; 2013: 251752


    Background. There is an urgent need to develop new treatment strategies and drugs for pancreatic cancer that is highly resistant to radio-chemotherapy. Aesculus hippocastanum (the horse chestnut) known in Chinese medicine as a plant with anti-inflammatory, antiedema, antianalgesic, and antipyretic activities. The main active compound of this plant is Escin (C54H84O23). Objective. To evaluate the effect of Escin alone and combined with chemotherapy on pancreatic cancer cell survival and to unravel mechanism(s) of Escin anticancer activity. Methods. Cell survival was measured by XTT colorimetric assay. Synergistic effect of combined therapy was determined by CalcuSyn software. Cell cycle and induction of apoptosis were evaluated by FACS analysis. Expression of NF- κ B-related proteins (p65, I κ Bα, and p-I κ Bα) and cyclin D was evaluated by western blot analysis. Results. Escin decreased the survival of pancreatic cancer cells with IC50 = 10-20 M. Escin combined with gemcitabine showed only additive effect, while its combination with cisplatin resulted in a significant synergistic cytotoxic effect in Panc-1 cells. High concentrations of Escin induced apoptosis and decreased NF- κ B-related proteins and cyclin D expression. Conclusions. Escin decreased pancreatic cancer cell survival, induced apoptosis, and downregulated NF- κ B signaling pathway. Moreover, Escin sensitized pancreatic cancer cells to chemotherapy. Further translational research is required.

    View details for DOI 10.1155/2013/251752

    View details for Web of Science ID 000214690100005

    View details for PubMedID 24282639

    View details for PubMedCentralID PMC3825277

  • Integrative oncology in the Middle East: from traditional herbal knowledge to contemporary cancer care ANNALS OF ONCOLOGY Ben-Arye, E., Schiff, E., Hassan, E., Mutafoglu, K., Lev-Ari, S., Steiner, M., Lavie, O., Polliack, A., Silbermann, M., Lev, E. 2012; 23 (1): 211-221
  • A Prospective, Controlled Study of the Botanical Compound Mixture LCS101 for Chemotherapy-Induced Hematological Complications in Breast Cancer ONCOLOGIST Yaal-Hahoshen, N., Maimon, Y., Siegelmann-Danieli, N., Lev-Ari, S., Ron, I. G., Sperber, F., Samuels, N., Shoham, J., Merimsky, O. 2011; 16 (9): 1197-1202


    This prospective, controlled study evaluated the safety, tolerability, and efficacy of the mixture of botanical compounds known as LCS101 in preventing chemotherapy-induced hematological toxicity in breast cancer patients.Female patients diagnosed with localized breast cancer were randomly allocated to receive treatment with either LCS101 or placebo capsules, in addition to conventional chemotherapy. The study intervention was initiated 2 weeks prior to the initiation of chemotherapy and continued until chemotherapy was completed, with participants receiving 2 g of LCS101 capsules thrice daily. Subjects were assessed for the development of hematological and nonhematological toxicities, as well as the tolerability and safety of the study intervention.Sixty-five breast cancer patients were recruited, with 34 allocated to LCS101 and 31 allocated to placebo treatment. Patients in the treatment group developed significantly less severe (grades 2-4) anemia (p < .01) and leukopenia (p < .03) when comparing grades 0-1 with grades 2-4, with significantly less neutropenia (p < .04) when comparing grades 0-2 with grades 3-4. This effect was more significant among patients undergoing a dose-dense regimen. No statistically significant effect was found with respect to nonhematological toxicities, and side effect rates were not significantly different between the groups, with no severe or life-threatening events observed in either group.The addition of LCS101 to anthracycline- and taxane-based chemotherapy is safe and well tolerated, and may significantly prevent some chemotherapy-induced hematological toxicities in early breast cancer patients. These results should encourage further larger and more extensive clinical trials.

    View details for DOI 10.1634/theoncologist.2011-0150

    View details for Web of Science ID 000295254100001

    View details for PubMedID 21712486

    View details for PubMedCentralID PMC3228177

  • Acupuncture and Chinese herbal treatment for women undergoing intrauterine insemination EUROPEAN JOURNAL OF INTEGRATIVE MEDICINE Sela, K., Lehavi, O., Buchan, A., Kedar-Shalem, K., Yavetz, H., Lev-ari, S. 2011; 3 (2): E77-E81
  • Delayed Effect of Acupuncture Treatment in OA of the Knee: A Blinded, Randomized, Controlled Trial EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE Miller, E., Maimon, Y., Rosenblatt, Y., Mendler, A., Hasner, A., Barad, A., Amir, H., Dekel, S., Lev-Ari, S. 2011; 2011: 1-5


    To assess the efficacy in providing improved function and pain relief by administering 8 weeks of acupuncture as adjunctive therapy to standard care in elderly patients with OA of the knee. This randomized, controlled, blinded trial was conducted on 55 patients with OA of the knee. Forty-one patients completed the study (26 females, 15 males, mean age ± SD 71.7 ± 8.6 years). Patients were randomly divided into an intervention group that received biweekly acupuncture treatment (n = 28) and a control group that received sham acupuncture (n = 27), both in addition to standard therapy, for example, NSAIDS, cyclooxygenase-2 inhibitors, acetaminophen, intra-articular hyaluronic acid and steroid injections. Primary outcomes measures were changes in the Knee Society Score (KSS) knee score and in KSS function and pain ratings at therapy onset, at 8 weeks (closure of study) and at 12 weeks (1 month after last treatment). Secondary outcomes were patient satisfaction and validity of sham acupuncture. There was significant improvement in all three scores in both groups after 8 and 12 weeks compared with baseline (P < .05). Significant differences between the intervention and control groups in the KSS knee score (P = .036) was apparent only after 12 weeks. Patient satisfaction was higher in the intervention group. Adjunctive acupuncture treatment seems to provide added improvement to standard care in elderly patients with OA of the knee. Future research should determine the optimal duration of acupuncture treatment in the context of OA.

    View details for DOI 10.1093/ecam/nen080

    View details for Web of Science ID 000293563800001

    View details for PubMedID 19124552

    View details for PubMedCentralID PMC3137589

  • Acupuncture for Treating Temporomandibular Disorder: Retrospective Study on Safety and Efficacy JOURNAL OF ACUPUNCTURE AND MERIDIAN STUDIES Noiman, M., Garty, A., Maimon, Y., Miller, U., Lev-Ari, S. 2010; 3 (4): 260-266


    This study aimed to retrospectively examine the efficacy and safety of acupuncture for the relief of pain originating from temporomandibular joint disorder and trigeminal neuralgia. Participants included patients suffering from trigeminal neuralgia or temporomandibular disorder with osseous pathology ruled out by panoramic X-rays. Participants received a series of 8-10 weekly acupuncture treatments and rated their pain via a visual analogue scale. From assessment of a total of 39 patients, analysis of pain severity before and after treatment showed that acupuncture intervention was highly beneficial for patients with temporomandibular joint disorder (88.6%, p < 0.01), compared with patients with trigeminal neuralgia in which there was only a minor effect (25%). The data also demonstrated that acupuncture was both efficacious in acute patients (91%, p < 0.01) and chronic patients (70%, p < 0.05) and elicited no side effects during the course of treatment. Acupuncture treatment was a safe and efficient methodology for relieving the pain of patients suffering from temporomandibular disorder with no detectable osseous joint component. Based on these results, a randomized clinical trial is being initiated at the Stomatologic Clinic at the Tel Aviv Sourasky Medical Center to assess the role of acupuncture in treating temporomandibular joint disorder.

    View details for DOI 10.1016/S2005-2901(10)60046-5

    View details for Web of Science ID 000214047400006

    View details for PubMedID 21185541

  • Effect of Chinese Herbal Therapy on Breast Cancer Adenocarcinoma Cell Lines JOURNAL OF INTERNATIONAL MEDICAL RESEARCH Maimon, Y., Karaush, V., Yaal-Hahoshen, N., Ben-Yosef, R., Ron, I., Vexler, A., Lev-Ari, S. 2010; 38 (6): 2033-2039


    Despite the widespread use of medicinal herbs to prevent and treat many diseases, including cancer, there are insufficient scientific data on the safety and efficacy of the majority of herbal therapies. The aim of this study was to assess the effect of a unique Chinese herbal therapy (CHT) from controlled manufactured concentrated powders, on an in vitro model of breast cancer. Three breast adenocarcinoma cell lines (MDA-231, MDA-453, T47D) were exposed to CHT for 72 h. Cell viability was assessed by XTT (sodium 3'-[1-(phenylaminocarbonyl)-3, 4-tetra zolium]-bis(4-methoxy-6-nitro) benzene sulphonic acid hydrate) assay. Apoptosis and cell cycle stage were determined by fluorescence-activated cell sorting (FACS) analysis. CHT decreased cell survival in a dose-dependent manner in all tested cell lines. FACS analysis of treated and non-treated T47D cells demonstrated that the inhibitory effect of CHT was associated with an increase in apoptosis. A randomized clinical trial is currently underway to investigate CHT as supplementary therapy for breast cancer patients receiving chemotherapy.

    View details for DOI 10.1177/147323001003800617

    View details for Web of Science ID 000288054400017

    View details for PubMedID 21227007

  • Curcumin: A Potential Radio-Enhancer in Head and Neck Cancer LARYNGOSCOPE Khafif, A., Lev-Ari, S., Vexler, A., Barnea, I., Starr, A., Karaush, V., Haif, S., Ben-Yosef, R. 2009; 119 (10): 2019-2026


    To investigate whether curcumin enhances the cytotoxic effect of radiotherapy in head and neck squamous cell carcinoma (HNSCC).HNSCC cell lines SCC-1, SCC-9, KB, as well as A431 cell line were treated with curcumin, irradiation, or their combination. Cell viability was evaluated by XTT assay. Cyclooxygenase-2 (COX-2), epithelial growth factor receptor (EGFR), and p-Erk1/2 were measured by Western blot analysis. CD-1 athymic nude mice with orthotopic implanted SCC-1 cells, were treated with control diet, curcumin containing diet, local single-dose radiation, or combination.Curcumin (IC50 range, 15-22 microM) and radiation inhibited cell viability in all cell lines were tested. The combination of curcumin and radiation resulted in additive effect. Curcumin decreased COX-2 expression and inhibited phosphorylation of EGFR in SCC-1 cells. In tumor-bearing mice the combination regimen showed a decrease in both tumor weight (25%, P = .09) and tumor size (15%, P = .23) compared to the nontreated mice.: Curcumin inhibited HNSCC cell growth and augmented the effect of radiation in vitro and in vivo. A possible mechanism is inhibition of COX-2 expression and EGFR phosphorylation.

    View details for DOI 10.1002/lary.20582

    View details for Web of Science ID 000270498100026

    View details for PubMedID 19655336

  • Invasive Breast Cancer Treated with Taxol and Epirubicin Neo-adjuvant Chemotherapy: The Role in the Outcome of the "Crosstalk" between Erb Receptors and p53 ANTICANCER RESEARCH Sarid, D., Ron, I. G., Shoshan, L., Barnea, I., Shina, S., Baratz, M., Greeenberg, J., Merimsky, O., Ben-Yosef, R., Lev-Ari, S., Keidar, Y., Yaal-Hahoshen, N. 2008; 28 (5B): 3147-3152


    To correlate p53 and ErbB receptors status with disease-free survival (DFS) and overall survival (OS) in locally advanced breast cancer.Sixty patients were included in a single-center, open-label, phase II trial (1998-2003). Analysis of Erb receptors and p53 status and estrogen receptor/progesterone receptor data were available for 33 patients. Neoadjuvant epirubicin 75 mg/m2 and paclitaxel 175-200 mg/m2 were administered every 21 days. The patients underwent surgery and radiation therapy and adjuvant chemo/hormonotherapy.Approximately two thirds of the patients demonstrated overexpression of ErbB receptors and had mutant p53 overexpression. The disease recurred in 11/33 patients and 7 died (median follow-up 56 months). Detrimental effects on OS were established in cases of combined defective p53 expression and ErbB1-ErbB3 heterodimeric receptor overexpression. In contrast, normal p53 together with the same overexpressed heterodimeric combination of ErbB receptors showed no statistically significant effect.In terms of the clinical impact of combinations of ErbB receptors with or without mutant p53, only the overexpressed various ErbB1-ErbB3 dimeric combinations and the ErbB1/ErbB2/ErbB3 triplet combination with mutated p53 were related to a significantly poorer outcome. This observation may help in the development of new strategies required for blocking these molecular pathways and improving the outcome of patients with locally advanced breast cancer.

    View details for Web of Science ID 000260555100051

    View details for PubMedID 19031973

  • Acupuncture Treatment in Geriatric Rehabilitation: A Retrospective Study JOURNAL OF ACUPUNCTURE AND MERIDIAN STUDIES Barad, A., Maimon, Y., Miller, E., Merdler, S., Goldray, D., Lerman, Y., Lev-ari, S. 2008; 1 (1): 54-57


    The main goal of geriatric rehabilitation reconditioning following an acute illness is rapid restoration of normal activity. Key elements are pain control, restoration of bowel function, sleep, appetite and general well being, alongside physical activity. The aim of this retrospective study was to assess the effect of acupuncture as an adjunct to medical and physical rehabilitation in geriatric patients. The setting was a university-affiliated large city general hospital. The participants comprised 27 consenting consecutive patients in a subacute geriatric rehabilitation department. The interventions consisted of biweekly acupuncture treatment in conjunction with medical and physical therapy. The outcome measures of pain, appetite, quality of sleep, bowel function and general well being were assessed using a 10-point Likert scale at the onset and close of treatment. The results showed that a significant post-treatment improvement was seen in pain (p=0.005), appetite (p=0.0034), bowel function (p=0.029) and general well being (p=0.0012) scores in patients' treatment when compared with pretreatment baseline scores. The "quality of sleep" score showed a trend towards improvement (p=0.073). In conclusion, acupuncture may be beneficial as an adjunctive treatment in geriatric postacute illness rehabilitation. Randomized controlled trials are needed to further assess the role of acupuncture as part of treatment management for restoring normal physical activity in geriatric patients.

    View details for DOI 10.1016/S2005-2901(09)60008-X

    View details for Web of Science ID 000214012700008

    View details for PubMedID 20633456

  • Anti-ERBb4 targeted therapy combined with radiation therapy in prostate cancer - Results of in vitro and invivo studies CANCER BIOLOGY & THERAPY Vexler, A., Lidawi, G., Loew, V., Barnea, I., Karaush, V., Lev-Ari, S., Shtabsky, A., Ben-Yosef, R. 2008; 7 (7): 1090-1094


    To evaluate the efficiency of anti ErbB4 targeted therapy combined with irradiation (XRT) over each modality alone in prostate cancer.Clones with high ErbB4 expression grew faster than those with low ErbB4 expression. XRT inhibited the growth of both expressive and non-expressive ErbB4 cells, while mAb inhibited only high ErbB4-expressing cells. The combination of XRT and mAb resulted in a 30% reduction of the survival of high ErbB4 expressing cells over XRT alone (p = 0.013). In tumor bearing mice the tumor size in the combined arm was 1 mm at 4 weeks compared to 2-3 mm and 4-5 mm in the radiation and mAb arms (p' value of 0.02 and 0.087 respectively).Clones with low and high expression of ErbB4 isolated by a limited dilution technique from an androgen-independent Cl-1 cell line were used. The cells from these clones were exposed to XRT (single dose of 2-6 Gy) and to anti-ErbB4 monoclonal antibody (mAb). The XTT test was used to measure cell survival. In addition, tumor-bearing nude mice were treated either by XRT, mAb or by a combined treatment. Tumor sizes were recorded at given time points.Anti ErbB4 combined with XRT is possibly more effective than each modality alone in prostate cancer.

    View details for DOI 10.4161/cbt.7.7.6167

    View details for Web of Science ID 000258524300020

    View details for PubMedID 18443429

  • Compositions for treatment of cancer and inflammation RECENT PATENTS ON ANTI-CANCER DRUG DISCOVERY Lev-Ari, S., Lichtenberg, D., Arber, N. 2008; 3 (1): 55-62


    Celecoxib (Celebrex, Pfizer, NY, USA) is a worldwide top branded COX-2-specific inhibitor. It was shown to provide relief of arthritic pain and inflammation and has recently been under investigation for the prevention and treatment of cancer. However, recent studies showed that long term use of high doses of celecoxib is associated with an increased cardiovascular toxicity. We discovered that the addition of curcumin, a natural COX-2 inhibitor, to celecoxib synergistically (up to 1000%) augments the growth inhibitory effects of celecoxib in in-vitro and in-vivo models of arthritis and cancer, thus rendering effective action of the drug at up to tenfold lower dose. This may pave the way for a novel strategy to treat arthritis and cancer because its effect [1] can be achieved in the serum of patients receiving standard anti inflammatory or anti-neoplastic dosages of celecoxib, and [2] involves a regimen with a very low profile of side effects. Preliminary data suggest that the combination is not limited only to celecoxib and that addition of curcumin to other NSAIDs such as sulindac, synergistically augments neoplastic cell growth inhibition. Based on these finding we received an IRB approval to evaluate celecoxib+curcumin in patients with osteoarthritis, pancreatic cancer and metastatic CRC. We hope to complete these novel human clinical trials, in 12-18 months.

    View details for Web of Science ID 000253328600006

    View details for PubMedID 18289124

  • ErbB-4 may control behavior of prostate cancer cells and serve as a target for molecular therapy PROSTATE Ben-Yosef, R., Starr, A., Karaush, V., Loew, V., Lev-Ari, S., Barnea, I., Lidawi, G., Shtabsky, A., Greif, Y., Yarden, Y., Vexler, A. 2007; 67 (8): 871-880


    To assess ErbB-4 expression in advanced human prostate cancer (PC) cell lines, the role of ErbB-4 in motility, migration, and proliferative/tumorigenic potential of PC cells, and efficacy of anti-ErbB-4 monoclonal antibody (Mab) treatment on PC cells in vitro and tumor growth in vivo.Established advanced human PC cell lines (PC-3, Cl-1, and Du-145) were evaluated for ErbB-4 expression. Several Cl-1 cell line clones expressing various levels of ErbB-4 were isolated, their motility, migration capacity, and in vitro proliferation as well as survival following Mab treatment were evaluated. Tumorigenicity and proliferation capacity of these clones in vivo and efficacy of Mab treatment on tumor growth were estimated by measurements of subcutaneous tumors developed in nude mice.PC cell lines studied express ErbB-4. Both PC-3 and Du-145 cell lines express high ErbB-4 levels; only 50% of Cl-1 cells express ErbB-4 with large heterogeneity. Cl-1 sub-clones highly expressing ErbB-4 showed increased cell motility, migration, and proliferation rate in vitro and enhanced growth in vivo, compared to clones with low ErbB-4 expression. Mab treatment inhibited the growth of cells expressing high but not low ErbB-4 levels in vitro and decreased the growth of subcutaneous tumors in nude mice generated by ErbB-4 highly expressing cells.High expression of ErbB-4 in prostate cancer Cl-1 cell clones correlated with high proliferative and migration capacity and high tumorigenic potential. The inhibitory effect of Mab on cell proliferation and on subcutaneous tumor growth suggests ErbB-4's potential as a target for molecular anticancer therapy.

    View details for DOI 10.1002/pros.20555

    View details for Web of Science ID 000246636300009

    View details for PubMedID 17440944

  • [Acupuncture as complementary medicine in patients with osteoarthritis of the knee]. Harefuah Lev-Ari, S., Hasner, A., Amir, H., Skott, T., Mosek, A., Miller, U., Maimon, Y. 2007; 146 (5): 354-406


    The popularity of integrative medicine, mainstream medical therapies combined with complementary and alternative medicine (CAM), increased in recent years in the USA and western countries. However, evidence based data on the efficacy of integrative medicine and safety is incomplete. Until recently, research on the use of acupuncture in osteoarthritis had methodological limitations such as low sample size. Recently, two large phase III randomized clinical studies were published on the efficacy of acupuncture in osteoarthritis of the knee. The studies have shown that acupuncture serves as an effective complementary treatment to standard care, improves function and provides pain relief for people with osteoarthritis of the knee. These studies confirm the results of previous studies on acupuncture as effective complementary treatment to standard care. This review summarizes the results of randomized clinical trials of acupuncture for treatment of osteoarthritis of the knee.

    View details for PubMedID 17674552

  • Down-regulation of PGE<sub>2</sub> by physiologic levels of celecoxib is not sufficient to induce apoptosis or inhibit cell proliferation in human colon carcinoma cell lines DIGESTIVE DISEASES AND SCIENCES Lev-Ari, S., Kazanov, D., Liberman, E., Ben-Yosef, R., Arber, N. 2007; 52 (4): 1128-1133


    This study was performed to evaluate whether down-regulation of prostaglandin E(2) (PGE(2)) synthesis by celecoxib treatment is associated with inhibition of cell growth in human colon carcinoma cell lines. Physiologic concentrations of celecoxib (5-10 microM) inhibited 80% to 90% of PGE(2) production in HT-29 cells that express high levels of COX-2 protein. In these concentrations, celecoxib had a minor inhibitory effect (20-30%) on cell growth. There was a significant change in induction of apoptosis only at higher concentrations of celecoxib (>20 microM). Treatment by low concentrations of celecoxib did not alter the levels of COX-1, beta-catenin, P(27), Bcl-2, and Bcl-x proteins. The effect of celecoxib on cell growth inhibition was higher on the COX-2-positive HT-29 cell line (IC(50)=20 microM) than on the COX-2 deficient SW-480 cell line (IC(50)=35 microM). In conclusion, inhibition of PGE(2) synthesis is an early, but not sufficient, step in the mechanism of celecoxib-mediated cell growth inhibition. These results support the need for additional evaluation of independent COX-2 pathways of celecoxib in chemoprevention of CRC.

    View details for DOI 10.1007/s10620-006-9619-x

    View details for Web of Science ID 000245131900046

    View details for PubMedID 17342386

  • Curcumin augments gemcitabine cytotoxic effect on pancreatic adenocarcinoma cell lines CANCER INVESTIGATION Lev-Ari, S., Vexler, A., Starr, A., Ashkenazy-Voghera, M., Greif, J., Aderka, D., Ben-Yosef, R. 2007; 25 (6): 411-418


    Gemcitabine, the first-line agent in pancreatic adenocarcinoma, has shown limited clinical benefit. Cyclooxygenase-2 (COX-2) represent one of the most promising targets for cancer prevention and treatment. In this study, we investigated whether the phytochemical curcumin, a natural COX-2 inhibitor, can potentiate gemcitabine effect on survival of human pancreatic cancer cells.P34 (high COX-2 expression) and Panc-1 (low COX-2 expression) pancreatic cancer cell lines were exposed to different concentrations of gemcitabine (0.1-10 microM), curcumin (0-50 microM), and their combination. Cell viability was evaluated by XTT assay. Cell cycle and apoptosis were assessed by flow cytometry. COX-2, EGFR, and p-ERK1/2 expression was measured by Western blot analysis.Curcumin increased the inhibitory effect of gemcitabine on cell viability as well as its pro-apoptotic effect in COX-2 positive, p34 cells, but not in COX-2 negative, Panc-1 cells. In p34 cells, combination of curcumin and gemcitabine downregulated both COX-2 and p-ERK1/2 in a dose-dependent manner.The increased cytotoxic effect of the combination on cell survival and on the induction of apoptosis in COX-2 expressing pancreatic cancer cells is probably associated with downregulation of COX-2 and p-ERK1/2 levels. This finding may contribute to the development of an effective treatment of pancreatic adenocarcinoma.

    View details for DOI 10.1080/07357900701359577

    View details for Web of Science ID 000249893700007

    View details for PubMedID 17882652

  • Long-term survival of a patient with widespread metastases from epithelial ovarian carcinoma receiving mind-body therapies: Case report and review of the literature INTEGRATIVE CANCER THERAPIES Lev-ari, S., Maimon, Y., Yaal-Hahoshen, N. 2006; 5 (4): 395-399


    Five-year survival of patients with stage IV epithelial ovarian carcinoma not treated after recurrence is almost non-existent in oncological literature. The authors report a patient almost 30 years after surgery of the primary epithelial ovarian carcinoma lesion and 15 years after recurrent disease and incomplete chemotherapy who is alive without evidence of disease. She received no conventional oncological therapy during the past 15 years but rather used many types of alternative medicine, predominantly mind body therapies. The authors review the relevant literature on this subject and describe what they believe to be the first report of long-term survival of such a patient.

    View details for DOI 10.1177/1534735406294221

    View details for Web of Science ID 000242121100015

    View details for PubMedID 17101768

  • Inhibition of pancreatic and lung adenocarcinoma cell survival by curcumin is associated with increased apoptosis, down-regulation of COX-2 and EGFR and inhibition of Erk1/2 activity ANTICANCER RESEARCH Lev-Ari, S., Starr, A., Vexler, A., Karaush, V., Loew, V., Greif, J., Fenig, E., Aderka, D., Ben-Yosef, R. 2006; 26 (6B): 4423-4430


    Several studies suggested that curcumin inhibits growth of malignant cells via inhibition of cyclooxygenase-2 (COX-2) activity. Other studies indicated that epidermal growth factor receptor (EGFR) is also inhibited by curcumin in vitro and in vivo. Moreover, recent investigations revealed an intracellular cross-talk between EGFR signaling and the COX-2 pathway. Our aim was to evaluate whether the curcumin inhibitory effect on the survival of cancer cells is associated with simultaneous down-regulation of COX-2 and EGFR and inhibition of Erk1/2 (extra-cellular signal regulated kinase) signaling pathway.Lung and pancreas adenocarcinoma cell lines co-expressing COX-2 and EGFR (PC-14 and p34, respectively) and those expressing EGFR but deficient in COX-2 (H1299 and Panc-1, respectively) were exposed for 72 h to curcumin (0-50 microM). Cell viability was assessed by the XTT assay. Apoptosis was determined by FACS analysis. COX-2, EGFR, ErbB-2 and p-Erk1/2 expressions were measured by Western blot analysis.Curcumin's inhibitory effect on survival and apoptosis of lung and pancreatic adenocarcinoma cell lines was significantly higher in the COX-2-expressing cells than in the COX-2-deficient cells. In the p34 and PC-14 cells, curcumin decreased COX-2, EGFR and p-Erk1/2 expressions in a dose-dependent manner. However, in the Panc-1 and H1299 cell lines, which did not express COX-2, curcumin did not affect EGFR levels.Curcumin co-inhibited COX-2 and EGFR expression and decreased Erk1/2 activity. This inhibition was associated with decreased survival and enhanced induction of apoptosis in lung and pancreatic adenocarcinoma cells.

    View details for Web of Science ID 000243040300046

    View details for PubMedID 17201164

  • ErbB4 increases the proliferation potential of human lung cancer cells and its blockage can be used as a target for anti-cancer therapy INTERNATIONAL JOURNAL OF CANCER Starr, A., Greif, J., Vexler, A., Ashkenazy-Voghera, M., Gladesh, V., Rubin, C., Kerber, G., Marmor, S., Lev-Ari, S., Inbar, M., Yarden, Y., Ben-Yosef, R. 2006; 119 (2): 269-274


    Clinical and experimental data suggest that ErbB-4, a member of the epidermal growth factor receptor family, may have a role in cancer progression and response to treatment. We found recently, using a retrospective clinical analysis, that expression of ErbB-4 receptor is correlated with metastatic potential and patient survival in non-small-cell lung cancer (NSCLC). The purpose of this work was to correlate the expression of the ErbB-4 and lung cancer cells growth in vitro and in vivo and to determine the therapeutic potential of a monoclonal antibody to ErbB-4 against lung cancer. For this aim, we ectopically expressed ErbB-4 in a human NSCLC cell line that did not express the ErbB-4 protein. Overexpression of ErbB-4 produced a constitutively activated ErbB-4 receptor. The transfected ErbB-4 positive clones showed an increased cell proliferation in vitro and in vivo in comparison with parental ErbB-4 negative cells and with the cells transfected by neomycin-resistant gene. A monoclonal antibody to ErbB-4 showed both an inhibitory effect on growth rate and an increasing apoptotic rate in the cells expressing ErbB-4. The results of the current study provide evidence that ErbB-4 plays a significant role in human lung cancer and may serve as a molecular target for anticancer therapy.

    View details for DOI 10.1002/ijc.21818

    View details for Web of Science ID 000238267300004

    View details for PubMedID 16463386

  • Curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in osteoarthritis synovial adherent cells RHEUMATOLOGY Lev-Ari, S., Strier, L., Kazanov, D., Elkayam, O., Lichtenberg, D., Caspi, D., Arber, N. 2006; 45 (2): 171-177


    Osteoarthritis (OA) is the Western world's leading cause of disability. Cyclo-oxygenase-2 (COX-2) inhibitors are efficient anti-inflammatory agents commonly used in the treatment of osteoarthritis. However, recent studies have shown that their long-term use may be limited due to cardiovascular toxicity. The anti-inflammatory efficacy of the phytochemical curcumin has been demonstrated in several in vitro and animal models. This study was undertaken to investigate whether curcumin augments the growth-inhibitory and pro-apoptotic effects of celecoxib in OA synovial adherent cells.OA synovial adherent cells were prepared from human synovial tissue collected during total knee replacement surgery. The cells were exposed to different concentrations of celecoxib (0-40 mum), curcumin (0-20 mum) and their combination. Flow cytometric analysis was used to measure the percentage of cells with a subdiploid DNA content, the hallmark of apoptosis. COX-2 activity was assessed by measuring production of prostaglandin E(2) by enzyme-linked immunoassay.A synergistic effect was observed in inhibition of cell growth when the cells were exposed to various concentrations of celecoxib combined with curcumin. The inhibitory effect of the combination on cell growth was associated with an increased induction of apoptosis. The synergistic effect was mediated through a mechanism that involves inhibition of COX-2 activity.This effect may enable the use of celecoxib at lower and safer concentrations, and may pave the way for a novel combination treatment in osteoarthritis and other rheumatological disorders.

    View details for DOI 10.1093/rheumatology/kei132

    View details for Web of Science ID 000234778300010

    View details for PubMedID 16249246

  • Celecoxib and curcumin additively inhibit the growth of colorectal cancer in a rat model DIGESTION Shpitz, B., Giladi, N., Sagiv, E., Lev-Ari, S., Liberman, E., Kazanov, D., Arber, N. 2006; 74 (3-4): 140-144


    Multiple studies have indicated that specific COX-2 inhibitors may prevent CRC. However, the long-term use of COX-2 inhibitors is not toxicity-free and may be limited due to its cardiovascular side effects. The present study was carried out to examine the chemopreventive effects of celecoxib and curcumin alone and in combination using the 1,2-dimethylhydrazine (DMH) rat model.Male rats were injected with DMH and randomly divided into four groups that consumed one of the following diets: (a) AIN-076 control diet; (b) AIN-076/curcumin (0.6%); (c) AIN-076/celecoxib (0.16%), or (d) AIN-076/celecoxib (0.16%) and curcumin (0.6%). Aberrant crypt foci (ACF) were identified by intensive staining with methylene blue in comparison to the surrounding normal crypts.The average number of ACF per rat colon was 64.2 +/- 3 in the control group, 39 +/- 5 and 47 +/- 10 for the curcumin- and celecoxib-treated group, respectively, and 24.5 +/- 6 in the group that had received both agents.In vivo, curcumin augments the growth inhibitory effect of celecoxib. This may be clinically important as this dose of celecoxib can be achieved in human serum following standard anti-inflammatory dosing of 100 mg.

    View details for DOI 10.1159/000098655

    View details for Web of Science ID 000245137800003

    View details for PubMedID 17228149

  • Down-regulation of prostaglandin E2 by curcumin is correlated with inhibition of cell growth and induction of apoptosis in human colon carcinoma cell lines. Journal of the Society for Integrative Oncology Lev-Ari, S., Maimon, Y., Strier, L., Kazanov, D., Arber, N. 2006; 4 (1): 21-6


    Several in vitro and in vivo studies have demonstrated an association between curcumin, a diferuloylmethane derived from the plant Curcuma longa, and colorectal cancer (CRC) prevention. Nevertheless, the molecular mechanism responsible for the chemopreventive effect of curcumin is not well understood and most probably involves several pathways. Several studies indicate that curcumin may exert its effect by specifically inhibiting the cyclooxygenase-2 (COX-2) isoenzyme, which is up-regulated in 40 to 50% of colorectal polyps and in up to 85% of CRCs. However, other studies have suggested that curcumin may also inhibit polyps formation by COX-2 independent mechanisms (eg, inhibition of ErbB-1, AkT). The aim of this study was to evaluate whether curcumin's effect on the inhibition of cell growth and induction of apoptosis in human colon carcinoma cell lines is correlated with inhibition of PGE2 synthesis and down-regulation of COX-2. HT29 cells (expressing COX-2) and SW480 (deficient of COX-2) were exposed to different concentrations (0-50 microM) of curcumin for 72 hours. Growth inhibition was assessed by Coulter counter. Cell viability was assessed by the ability of metabolically active cells to reduce tetrazolium salt to colored formazan compounds (tetrazolium salt assay). Apoptosis was measured by two independent methods: flow cyto-metric analysis and 4'-6-Diamidino-2-phenylindole (DAPI) staining. Activity of COX-2 was evaluated by measuring prostaglandin E2 (PGE2) concentration using a specific enzyme-linked immunoassay. COX-1 and COX-2 expressions were measured by Western blot analysis. There was a significant difference between curcumin effect on COX-2-expressing (HT29: inhibitory concentration 50% [IC50] = 15 microM) and COX-2-deficient (SW480: IC50 = 40 microM) cells. Similarly, induction of apoptosis was higher in cells expressing COX-2. Western blot analysis and PGE2 immunoassay showed that curcumin inhibited COX-2 protein activity and expression in a dose-dependent manner. In conclusion, inhibition of cell survival and induction of apoptosis by curcumin in colorectal adenocarcinoma cell lines is associated with the inhibition of PGE2 synthesis and down-regulation of COX-2.

    View details for PubMedID 16737669

  • Curcumin synergistically potentiates the growth inhibitory and pro-apoptotic effects of celecoxib in pancreatic adenocarcinoma cells Lev-Ari, S., Zinger, H., Kazanov, D., Yona, D., Ben-Yosef, R., Starr, A., Figer, A., Arber, N. ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER. 2005: S276-S280


    Adenocarcinoma of the Pancreas is a leading cause of cancer-related mortality, accounting for an estimated 30,000 deaths per year in the United States. Multiple studies have indicated that specific cyclooxygenase-2 (COX-2) inhibitors may serve in the prevention and treatment of a variety of malignancies including pancreatic adenocarcinoma. Recent studies had shown that the long-term use of high concentration of COX-2 inhibitors is not toxic free and may be limited due to serious gastrointestinal and cardiovascular side effects. The chemopreventive efficacy of the phytochemical, curcumin has been demonstrated in several in vitro and animal models. In this study we investigated whether curcumin potentiates the growth inhibition effect of a COX-2 inhibitor (celecoxib, Pfizer, NY, USA) in human pancreatic cancer cells.P-34 (expressing high levels of COX-2), and MIAPaCa (expressing low levels of COX-2) and Panc-1 (no expression of COX-2) evaluated cell lines were exposed to different concentrations of celecoxib (0-40 microM), curcumin (0-20 microM) and their combination. Cell viability was by XTT assay. Apoptosis was assessed by flow cytometry and COX-2 expression was measured by Western blotting analysis.In P-34 cells, curcumin synergistically potentiated the inhibitory effect of celecoxib on cell growth. The growth inhibition was associated with inhibition of proliferation and induction of apoptosis. Western blot analysis showed that COX-2 expression was down-regulated by the combination therapy.Curcumin synergistically augments the growth inhibition inserted by celecoxib in pancreatic cancer cells expressing COX-2. The synergistic effect was mediated through inhibition of COX-2. This may enable the use of celecoxib at lower and safer concentrations and may pave the way for a more effective treatment in this devastating disease.

    View details for DOI 10.1016/S0753-3322(05)80045-9

    View details for Web of Science ID 000234423600005

    View details for PubMedID 16507392

  • Celecoxib and curcumin synergistically inhibit the growth of colorectal cancer cells CLINICAL CANCER RESEARCH Lev-Ari, S., Strier, L., Kazanov, D., Madar-Shapiro, L., Dvory-Sobol, H., Pinchuk, Marian, B., Lichtenberg, D., Arber, N. 2005; 11 (18): 6738-6744


    Multiple studies have indicated that cyclooxygenase-2 (COX-2) inhibitors may prevent colon cancer, which is one of the leading causes of cancer death in the western world. Recent studies, however, showed that their long-term use may be limited due to cardiovascular toxicity. This study aims to investigate whether curcumin potentiates the growth inhibitory effect of celecoxib, a specific COX-2 inhibitor, in human colon cancer cells.HT-29 and IEC-18-K-ras (expressing high levels of COX-2), Caco-2 (expressing low level of COX-2), and SW-480 (no expression of COX-2) cell lines were exposed to different concentrations of celecoxib (0-50 micromol/L), curcumin (0-20 micromol/L), and their combination. COX-2 activity was assessed by measuring prostaglandin E(2) production by enzyme-linked immunoassay. COX-2 mRNA levels were assessed by reverse transcription-PCR.Exposure to curcumin (10-15 micromol/L) and physiologic doses of celecoxib (5 micromol/L) resulted in a synergistic inhibitory effect on cell growth. Growth inhibition was associated with inhibition of proliferation and induction of apoptosis. Curcumin augmented celecoxib inhibition of prostaglandin E(2) synthesis. The drugs synergistically down-regulated COX-2 mRNA expression. Western blot analysis showed that the level of COX-1 was not altered by treatment with celecoxib, curcumin, or their combination.Curcumin potentiates the growth inhibitory effect of celecoxib by shifting the dose-response curve to the left. The synergistic growth inhibitory effect was mediated through a mechanism that probably involves inhibition of the COX-2 pathway and may involve other non-COX-2 pathways. This synergistic effect is clinically important because it can be achieved in the serum of patients receiving standard anti-inflammatory or antineoplastic dosages of celecoxib.

    View details for DOI 10.1158/1078-0432.CCR-05-0171

    View details for Web of Science ID 000232016100042

    View details for PubMedID 16166455

  • Establishment and characterization of a pancreatic carcinoma cell line derived from malignant pleural effusion ONCOLOGY Starr, A. N., Vexler, A., Marmor, S., Konik, D., Ashkenasi-Voghera, M., Lev-Ari, S., Greif, Y., Ben-Yosef, R. 2005; 69 (3): 239-245


    A novel cell line, designated p34, was developed from the malignant pleural effusion of a patient with carcinoma of pancreas. The objective of this work was to characterize this cell line.The in vitro studies included karyotype analysis, immunohistochemistry, XTT cell proliferation assay, analysis of the cell cycle by FACS and cell sensitivity to chemotherapeutic drugs and irradiation. Subcutaneous and intra-spleen inoculations into nude mice were carried out to study the tumorigenicity and the metastatic tendency of this cell line.The p34 cell line showed typical morphological characteristics of epithelial pancreatic tumor cells. The cells were hyperdiploid with a modal number of 48, and had two markers, deletion in the short arm of chromosome 2 and duplication of the short arm of chromosome 8. The doubling time was 16 h. Subcutaneous inoculation of the cells into nude mice yielded 100% tumorigenicity, and intra-spleen inoculation resulted in extensive intra-abdominal spread. The antiproliferative effect of chemotherapy (gemcitabine, cisplatin, taxol and vinorelbine), chemopreventive agents (celecoxib and curcumin) and radiotherapy showed dose-dependent cytotoxicity.This p34 cell line can be used as a new model for studying various aspects of the biology of human pancreatic cancer and potential treatment approaches for the disease.

    View details for DOI 10.1159/000088071

    View details for Web of Science ID 000232490500006

    View details for PubMedID 16141719