Identifying lifestyle factors associated to co-morbidity of obesity and psychiatric disorders, a pilot study

Obesity and psychiatric disorders are linked through a bidirectional association. Obesity rates have tripled globally in the past decades, and it is predicted that by 2025, one billion people will be affected by obesity, often with a co-morbidity such as depression. While this co-morbidity seems to be a global health issue, lifestyle factors associated to it differ between countries and are often attributed to more than one factor. Prior obesity studies were performed in Western populations; this is the first study that investigates lifestyle factors relating to obesity and mental health of the diverse population in Qatar, a country that has witnessed tremendous lifestyle change in a short time. In this pilot study, we surveyed 379 respondents to assess and compare the lifestyles of Qatar residents to the global population. However due to the high proportion of responses from the United Kingdom (UK) residents, we have made comparisons between Qatar residents and UK residents. We used chi-square analysis, spearman rank correlation and logistic regression to compare the lifestyle factors of individuals suffering from both increased BMI and mental health conditions. The types of food consumed, stress, exercise frequency and duration, alcohol and tobacco consumption, and sleep duration, were explored and results argue that different lifestyle factors can contribute to the same health condition, suggesting different mechanisms involved. We found that both groups reported similar sleep durations (p = 0.800), but that perception of sleep (p = 0.011), consumption of alcohol (p = 0.001), consumption of takeaway food (p = 0.007), and physical activity significantly varied between the groups (p = 0.0001). The study examined the predictors of comorbidity in Qatar as well as UK populations using multivariate logistic regression analysis. The result of the study showed no statistical association between comorbidity and the predictors drinking habit, smoking, physical activity, vegetable consumption, eat outs, and sleep perception for the Qatar population, and for the combined population. This study, however showed a significant association (p = 0.033) between sleep perception and comorbidity for the UK population. We conclude that further analysis is needed to understand the relationship between specific lifestyle factors and multimorbidity in each country

IL-7 promotes T cell proliferation through destabilization of p27Kip1

Interleukin (IL)-7 is required for survival and homeostatic proliferation of T lymphocytes. The survival effect of IL-7 is primarily through regulation of Bcl-2 family members; however, the proliferative mechanism is unclear. It has not been determined whether the IL-7 receptor actually delivers a proliferative signal or whether, by promoting survival, proliferation results from signals other than the IL-7 receptor. We show that in an IL-7–dependent T cell line, cells protected from apoptosis nevertheless underwent cell cycle arrest after IL-7 withdrawal. This arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 through a posttranslational mechanism. Overexpression of p27Kip1 induced G1 arrest in the presence of IL-7, whereas knockdown of p27Kip1 by small interfering RNA promoted S phase entry after IL-7 withdrawal. CD4 or CD8 T cells transferred into IL-7–deficient hosts underwent G1 arrest, whereas 27Kip1-deficient T cells underwent proliferation. We observed that IL-7 withdrawal activated protein kinase C (PKC)θ and that inhibition of PKCθ with a pharmacological inhibitor completely blocked the rise of p27Kip1 and rescued cells from G1 arrest. The conventional pathway to breakdown of p27Kip1 is mediated by S phase kinase-associated protein 2; however, our evidence suggests that PKCθ acts via a distinct, unknown pathway inducing G1 arrest after IL-7 withdrawal from T cells. Hence, IL-7 maintains T cell proliferation through a novel pathway of p27Kip1 regulation

Downregulation of IGF-1 receptor occurs after hepatic linage commitment during hepatocyte differentiation from human embryonic stem cells

AbstractThe insulin-like growth factor 1 receptor (IGF-1R) has been suggested to be involved in hepatocyte differentiation. Human hepatocyte cancer cells and stem cells are known to express IGF-1R whereas normal hepatocytes do not. In the present study we optimized a differentiation protocol and verified the different stages by established markers. The expression levels of IGF-1R and major downstream signaling proteins during differentiation from human embryonic stem cells (hESC) to mature hepatocytes were investigated. We could only demonstrate a minor decrease in IGF-1R expression during endodermal differentiation compared to hESC, but declined substantially (>50%) after hepatic lineage commitment during the hepatocyte specification and maturation stages. This downregulation was paralleled by an upregulation of ERK 1/2, AKT and insulin substrate-1. Neither inhibition nor activation of IGF-1R had any essential effect on endoderm differentiation of human embryonic stem cells. Therefore, our data suggest that IGF-1R downregulation may have a regulatory impact after initiation of hepatic lineage commitment

Cdk2 as a Master of S phase Entry: Fact or Fake?

It has long been believed that Cdk2 and its activator cyclin E play essential roles in the progression of the mitotic cell cycle. However, recent studies using knockout mouse models revealed that neither Cdk2 nor cyclin E are essential in vivo. The purpose of this Perspective is to compare both Cdk2 and cyclin E knockout mice models and to discuss potential mechanisms driving the cell cycle in the absence of Cdk2 or cyclin E. Particular emphasis is placed on possible non-catalytic roles of cyclin E, the expression and activity of the second cyclin binding partner of Cdk2, cyclin A, as well as on the expression and degradation of the Cdk2 inhibitor p27Kip1 in the absence of Cdk2

Abstract 2349: Sensitivity and resistance to cell cycle and IGF-1R inhibitors in rhabdomyosarcoma

Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and young adults. The five-year survival rate for RMS has hardly improved over the last three decades despite intensive and toxic chemotherapy, radiotherapy with surgery. Therefore, novel treatment approaches are required to change these outcomes. RMS has two major subtypes, embryonal RMS (ERMS) and alveolar RMS (ARMS). ARMS, the more aggressive subtype, is characterized by translocations that fuse two transcription factor-encoding genes; creating novel PAX3/PAX7-FOXO1 fusion proteins. The PAX3-FOXO1 is highly expressed in the G2 phase of the cell cycle, allowing the cell to divide following a sustained checkpoint arrest despite DNA damage induced by chemotherapy, suggesting that PAX3-FOXO1 may enhance the survival of tumor cells in response to chemotherapy. Many cell cycle regulators are altered in RMS, including CDK2, CDK4 and p53. Furthermore, RMS cells are highly dependent on the insulin-like growth factor -1 receptor (IGF-1R) signaling, however, IGF-1R targeting was not successful in the clinic. Therefore, targeting key cell cycle regulators individually or in combination with IGF-1R inhibition may expand the available therapeutic options for RMS. Purpose: The goal of the present study was to investigate the cytotoxicity of 15 small molecule inhibitors targeting the IGF-1R and cell cycle regulators in RMS cell lines and to determine potential mechanisms of drug sensitivity or resistance. Methods and Results: Seven RMS cell lines including ERMS and ARMS were studied. The IC50 values were determined for the following targeting compounds: linsitinib, BMS-754807 and picropodophyllin (PPP) (IGF-1R), riobociclib and palbociclib (CDK4/6), dinaciclib and flavopiridol (pan CDK inhibitors), BS-181HCL (CDK7), MK-1775 (WEE-1), MK-8776 (CHK1), alisertib (AURKA) and volasertib (PLK1). The most potent compounds with IC50&amp;lt; 10 nM were dinaciclib and volasertib. The ARMS cell lines were resistant to alisertib in comparison to the ERMS cell lines. Most cell lines were sensitive to flavopiridol, MK-1775, BMS-754807 and PPP with IC50&amp;lt; 100 nM, and relatively resistant to BS-181 HCL, linsitinib, R0-3306 and MK-8776 with IC50 (1-70 μM). Palbociclib and BMS-754807 showed a synergistic effect in some RMS cell lines. Ongoing studies are focusing on determining the mechanisms of interaction of these two compounds through studying cell cycle, apoptosis, and mRNA and protein expression of key regulators in the IGF-1R and RB pathways. Conclusion: These data demonstrate that dinaciclib, volasertib, flavopiridol, MK-1775, BMS-754807 and PPP are highly cytotoxic in RMS cell lines. The CDK4/6 inhibitor palbociclib may sensitize selected RMS cell lines to IGF-1R inhibitors. Targeting selected cell cycle regulators individually, or in combination with IGF-1R inhibitors may thus provide an efficacious treatment approach to be further validated in RMS patients with poor outcome. Citation Format: Justin Montoya, David W. Lee, Eiman Aleem. Sensitivity and resistance to cell cycle and IGF-1R inhibitors in rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2349. doi:10.1158/1538-7445.AM2017-2349</jats:p