GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Aromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER⁺) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER⁺breast cancer cells</p> <p>Methods</p> <p>We used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined.</p> <p>Results</p> <p>GP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole.</p> <p>Conclusion</p> <p>Our findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER⁺breast cancer.</p

Ibudilast for alcohol use disorder: study protocol for a phase II randomized clinical trial.

BackgroundAlcohol use disorder (AUD) is a chronic and relapsing condition for which current pharmacological treatments are only modestly effective. The development of efficacious medications for AUD remains a high research priority with recent emphasis on identifying novel molecular targets for AUD treatment and to efficiently screen new compounds aimed at those targets. Ibudilast, a phosphodiesterase inhibitor, has been advanced as a novel addiction pharmacotherapy that targets neurotrophin signaling and neuroimmune function.MethodsThis study will conduct a 12-week, double-blind, placebo controlled randomized clinical trial of ibudilast (50 mg BID) for AUD treatment. We will randomize 132 treatment-seeking men and women with current AUD. We will collect a number of alcohol consumption outcomes. Primary among these is percent heavy drinking days (PHDD); secondary drinking outcomes include drinks per day, drinks per drinking day, percent days abstinent, percent subjects with no heavy drinking days, and percent subjects abstinent, as well as measures of alcohol craving and negative mood. Additionally, participants will have the option to opt-in to a neuroimaging session in which we examine the effects of ibudilast on neural activation to psychosocial stress and alcohol cues. Finally, we will also collect plasma levels of proinflammatory markers, as well as subjective and biological (salivary cortisol) markers of stress response.DiscussionThis study will further develop ibudilast, a safe and promising novel compound with strong preclinical and clinical safety data for AUD, and will probe biological mechanisms underlying the effects of Ibudilast on stress, neuroinflammation, and alcohol cue-reactivity and craving. If ibudilast proves superior to placebo in this study, it will set the stage for a confirmatory multi-site trial leading to FDA approval of a novel AUD treatment.Trial registrationClinicalTrials.gov NCT03594435 "Ibudilast for the Treatment of Alcohol Use Disorder". Registered on 20 July 2018

Ibudilast for alcohol use disorder: study protocol for a phase II randomized clinical trial.

BackgroundAlcohol use disorder (AUD) is a chronic and relapsing condition for which current pharmacological treatments are only modestly effective. The development of efficacious medications for AUD remains a high research priority with recent emphasis on identifying novel molecular targets for AUD treatment and to efficiently screen new compounds aimed at those targets. Ibudilast, a phosphodiesterase inhibitor, has been advanced as a novel addiction pharmacotherapy that targets neurotrophin signaling and neuroimmune function.MethodsThis study will conduct a 12-week, double-blind, placebo controlled randomized clinical trial of ibudilast (50 mg BID) for AUD treatment. We will randomize 132 treatment-seeking men and women with current AUD. We will collect a number of alcohol consumption outcomes. Primary among these is percent heavy drinking days (PHDD); secondary drinking outcomes include drinks per day, drinks per drinking day, percent days abstinent, percent subjects with no heavy drinking days, and percent subjects abstinent, as well as measures of alcohol craving and negative mood. Additionally, participants will have the option to opt-in to a neuroimaging session in which we examine the effects of ibudilast on neural activation to psychosocial stress and alcohol cues. Finally, we will also collect plasma levels of proinflammatory markers, as well as subjective and biological (salivary cortisol) markers of stress response.DiscussionThis study will further develop ibudilast, a safe and promising novel compound with strong preclinical and clinical safety data for AUD, and will probe biological mechanisms underlying the effects of Ibudilast on stress, neuroinflammation, and alcohol cue-reactivity and craving. If ibudilast proves superior to placebo in this study, it will set the stage for a confirmatory multi-site trial leading to FDA approval of a novel AUD treatment.Trial registrationClinicalTrials.gov NCT03594435 "Ibudilast for the Treatment of Alcohol Use Disorder". Registered on 20 July 2018

Endotoxin for Alcohol Research: A Call for Experimental Medicine Using Lipopolysaccharide Challenge.

Studies of inflammation in alcohol use disorder (AUD) are overwhelmingly preclinical, and translation to clinical samples is necessary. Endotoxin administration has been used successfully in humans to study mood disorders, offering a translational, reliable and safe model that may be validated in AUD research. We argue for the use of endotoxin challenge to elucidate the interplay between AUD and inflammation

The impact of social media on medical professionalism: a systematic qualitative review of challenges and opportunities

Background: The rising impact of social media on the private and working lives of health care professionals has made researchers and health care institutions study and rethink the concept and content of medical professionalism in the digital age. In the last decade, several specific policies, original research studies, and comments have been published on the responsible use of social media by health care professionals. However, there is no systematic literature review that analyzes the full spectrum of (1) social media–related challenges imposed on medical professionalism and (2) social media–related opportunities to both undermine and improve medical professionalism. Objective: The aim of this systematic qualitative review is to present this full spectrum of social media–related challenges and opportunities. Methods: We performed a systematic literature search in PubMed (restricted to English and German literature published between 2002 and 2011) for papers that address social media–related challenges and opportunities for medical professionalism. To operationalize “medical professionalism”, we refer to the 10 commitments presented in the physicians’ charter “Medical professionalism in the new millennium” published by the ABIM Foundation. We applied qualitative text analysis to categorize the spectrum of social media–related challenges and opportunities for medical professionalism. Results: The literature review retrieved 108 references, consisting of 46 original research studies and 62 commentaries, editorials, or opinion papers. All references together mentioned a spectrum of 23 broad and 12 further-specified, narrow categories for social media–related opportunities (n=10) and challenges (n=13) for medical professionalism, grouped under the 10 commitments of the physicians’ charter. Conclusions: The accommodation of the traditional core values of medicine to the characteristics of social media presents opportunities as well as challenges for medical professionalism. As a profession that is entitled to self-regulation, health care professionals should proactively approach these challenges and seize the opportunities. There should be room to foster interprofessional and intergenerational dialogue (and eventually guidelines and policies) on both challenges and opportunities of social media in modern health care. This review builds a unique source of information that can inform further research and policy development in this regard

Pain catastrophizing predicts alcohol craving in heavy drinkers independent of pain intensity

BackgroundChronic pain and alcohol use disorder (AUD) are often co-occurring conditions. Pain catastrophizing, an emotional component of pain, and pain intensity are related to alcohol use as a coping mechanism; however, how pain interacts with tonic alcohol craving is an understudied area. This study sought to determine the unique and independent effects of pain intensity and pain catastrophizing on alcohol craving in heavy drinkers.MethodNon-treatment seeking heavy drinkers (n = 128) completed self-report measures of pain (both intensity and catastrophizing), depression, alcohol use and problems, and reasons for heavy drinking. A hierarchical regression examined the unique contribution of pain intensity to alcohol craving. Depression, pain catastrophizing, and alcohol use measures were added to the hierarchical model in sequential blocks.ResultsThe final model of the hierarchical regression demonstrated that pain catastrophizing has an independent effect on alcohol craving over and above demographic, pain intensity, depression, and alcohol measures. Exploratory analyses suggest that individuals in the high intensity pain grade have higher levels of depression symptomology, pain catastrophizing, alcohol use and problems, as well as engaging in heavy drinking to "feel normal" compared to the no pain and low intensity pain grades.ConclusionsThese results demonstrate that pain catastrophizing predicts alcohol craving independent of self-reported chronic pain intensity. Individuals with high intensity chronic pain have more severe alcohol use and mood-related symptomology. Upon replication in clinical samples, these findings can inform clinical care for pain management