Abstract
STING (Stimulator of Interferon Genes) is a master regulator of type I interferons and a key mediator of innate immunity. Activation of STING provides two critical anti-tumor responses – (1) ...The “spark” for initiating a robust innate immune response and (2) Priming and activation of a potent T cell mediated anti-tumor adaptive response. By serving as a bridge between the two arms of the immune system, activation of STING has the potential to transform the tumor microenvironment from immunologically “cold” to “hot” (inflamed), making otherwise resistant tumors respond to checkpoint blockade as well as other T cell targeting immunotherapies. Many preclinical and clinical drug discovery programs targeting STING activation are based on modifications of the naturally occurring cyclic dinucleotide (CDN) agonists. However, the CDN molecules suffer from poor drug-like properties and consequently cannot be delivered systemically. Thus, the benefits of STING activation by these first generation CDNs will be limited to only a subset of tumors that are accessible to intratumoral injection. The large, polar and charged binding site as well as the mechanism of activation of STING present unique drug discovery challenges to designing a small molecule that can induce the optimal, active conformation of the STING dimer while maintaining the physical-chemical properties required for systemic exposure. Using our proprietary physics-driven discovery engine with our integrative chemistry/biophysics/biology approach we have developed novel small molecule agonists of STING that exhibit selective and potent activity across all known isoforms of the human protein. Our small molecule agonist rapidly activates the STING/TBK1/IRF3 pathway (phosphorylation and translocation) and induces the expression of type I IFN in cells in a STING-dependent manner. Treatment of primary immune cells from healthy human donors results in the activation of dendritic cells and upregulation of costimulatory markers. Drug characteristics and STING pharmacology allow for unique dosing paradigm in vivo with robust induction of type I IFN after intravenous (i.v.) administration. A single i.v. dose produces potent and durable anti-tumor immunity and complete tumor regression in mice bearing syngeneic tumors. Activation of tumor directed T cell response provides long term protection against tumor re-challenge and effective systemic immunity. Our work highlights the tremendous potential of a small molecule STING agonist as a well-tolerated, systemically delivered cancer immunotherapeutic.
Citation Format: Meghana M Kulkarni, Timothy Dwight, Kristen Marino, Bryce K Allen, Mohammed Taimi, Cecilia Bastos, Sujen Lai, Cheryl Koh, Ramya Samant, Bethany Tesar, Huang Huang, Brian Chamberlain, James M Rice, Dazhi Tan, Zhixiong Lin, Sharon Shechter, Stella Li, Sam Sparks, Holly Soutter, Steven Swann, Woody Sherman, Christopher Winter. True small molecule STING agonist generates systemic and potent anti-tumor immunity required for effective cancer immunotherapy abstract. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A20. doi:10.1158/1535-7163.TARG-19-LB-A20
Abstract
Inhibitors of the BET family of bromodomain proteins have been shown to be growth inhibitory across a spectrum of tumor types due to their ability to regulate the expression of key survival ...and cell fate determining genes such as c-myc. In addition to their role in cancer, studies using genetic knockdown and small molecule inhibitors have demonstrated that targeting BET proteins controls the expression of pro-inflammatory cytokine genes in macrophages and is therapeutic in models of acute inflammation. These data suggest that in addition to their tumor intrinsic effects, BET inhibitors may also regulate the cytokine milieu within the tumor microenvironment and have immunomodulatory activity in cancer. To study this aspect, we evaluated INCB054329, a novel and selective BET inhibitor currently in Phase 1 trials, alone and in combination either with epacadostat, a highly selective IDO1 inhibitor, or with PD-1/PD-L1 axis blockade in syngeneic tumor models using immunocompetent animals. When used alone, INCB054329 suppressed a panel of cytokines and chemokines in a whole blood assay, confirming that INCB054329 can antagonize a pro-inflammatory response. The potency of INCB054329 in reducing the levels of these inflammatory mediators in the whole blood assay was similar to that for inhibition of c-myc, suggesting that the effects were on-target. INCB054329 was capable of inhibiting the growth of multiple syngeneic tumor models in immunocompetent mice, whereas only modest tumor growth inhibition was observed in immunodeficient mice and a lack of activity was observed in vitro, supporting the immunomodulatory activity of the compound. Because maximal in vivo tumor growth inhibition required an intact immune system, we investigated the impact of INCB054329 on various immune cell subsets, both in vitro and in vivo. Of note, increases in effector T cell populations were observed and efforts are ongoing to further characterize the tumor infiltrating immune cells following INCB054329 treatment. The mechanistic complimentarity of this novel BET inhibitor-mediated immunomodulation was also evaluated in combination with other therapeutically relevant mechanisms, including IDO1 inhibition and PD-1 axis blockade. Enhanced efficacy was observed with all INCB054329-containing regimens. These data demonstrate for the first time that BET inhibition can suppress tumor growth through both tumor-intrinsic and immune modulatory mechanisms, and support the potential of epigenetic-based, immunotherapy combinations as a novel approach to cancer therapy.
Citation Format: Holly K. Koblish, Michael Hansbury, Leslie Hall, Liang-Chuan Wang, Yue Zhang, Maryanne Covington, Timothy Burn, Mark Rupar, Christine Gardiner, Thomas Condamine, Kerri Lasky, Matthew C. Stubbs, Eddy Yue, Richard Sparks, Richard Sparks, Thomas Maduskuie, Andrew P. Combs, Gregory Hollis, Reid Huber, Phillip CC Liu, Peggy Scherle. The BET inhibitor INCB054329 enhances the activity of checkpoint modulation in syngeneic tumor models. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4904.
THE NATIONAL LESBIAN FAMILY STUDY Gartrell, Nanette; Hamilton, Jean; Banks, Amy ...
American journal of orthopsychiatry,
April 1996, Letnik:
66, Številka:
2
Journal Article
Recenzirano
This first report from a longitudinal study of 84 lesbian families, 70 of which include a co-mother as well as a birthmother whose child was conceived by donor insemination, presents interview data ...on parental relationships, social supports, pregnancy motives and preferences, stigmatization concerns, and coping strategies. Methodological limitations of studying this special population are noted, and plans for follow-up interviews over the course of 25 years are outlined.
Abstract
Indoleamine 2,3-dioxygenase (IDO or IDO1) mediates the oxidation of tryptophan, an amino acid essential for cell proliferation and survival. Inhibition of IDO activity or expression has ...shown therapeutic potential in preclinical models of immunodeficiency-associated abnormalities including cancer. Here we report the identification of INCB024360, a novel, potent and selective small molecule inhibitor of IDO1, and the investigation of its effects on the proliferation and activation of various immune cells in vitro as well as its anti-tumor activity in preclinical tumor models. In multiple cell-based assays, INCB024360 potently inhibits human IDO1 with an IC50 of approximately 10 nM - the most potent IDO1 inhibitor published thus far. INCB024360 is IDO1 selective and has little activity against other related enzymes including IDO2, TDO or tryptophan transporters. In co-culture systems of human allogeneic lymphocytes with either dendritic cells or tumor cells, inhibition of IDO1 by INCB024360 increases the proliferation of T and NK cells, as well as IFN- production. INCB024360 addition also reduces the generation of regulatory T cells. Interestingly, IDO1 expression promotes dendritic cell apoptosis while addition of INCB024360 reverses this and increases the number of CD86high cells within the IDO+ DC population, potentially representing a novel mechanism by which IDO1 inhibition can promote T cell activation. In vivo, INCB024360 inhibits tryptophan catabolism in tumors and tumor draining lymph nodes and controls tumor growth either alone or in combination with chemotherapeutic agents in multiple tumor models. The ability to reduce tumor growth is dependent on a functional immune system, consistent with the proposed mechanism of action. Finally, an analysis of kynurenine/tryptophan levels in patient blood samples affirms that the IDO activity is elevated in multiple tumor types. Collectively, these data suggest that INCB024360, a potent IDO1 selective inhibitor, has the potential to be a novel and effective immunotherapeutic agent for cancer treatment.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C106.
Too often, populations experiencing the greatest burden of disease and disparities in health outcomes are left out of or ineffectively involved in academic-led efforts to address issues that impact ...them the most. Community-based participatory research (CBPR) is an approach increasingly being used to address these issues, but the science of CBPR is still viewed by many as a nascent field. Important to the development of the science of CBPR is documentation of the partnership process, particularly capacity building activities important to establishing the CBPR research infrastructure. This paper uses a CBPR Logic Model as a structure for documenting partnership capacity building activities of a long-term community-academic partnership addressing public health issues in Arkansas, U.S. Illustrative activities, programs, and experiences are described for each of the model's four constructs: context, group dynamics, interventions, and outcomes. Lessons learned through this process were: capacity building is required by both academic and community partners; shared activities provide a common base of experiences and expectations; and creating a common language facilitates dialogue about difficult issues. Development of community partnerships with one institutional unit promoted community engagement institution-wide, enhanced individual and partnership capacity, and increased opportunity to address priority issues.
Wal★Mart World Brunn, Stanley D
2006, 20060831, 2006-08-31
eBook
Now that Wal-Mart has conquered the US, can it conquer the world? As Wal-Mart World shows, the corporation is certainly trying. For a number of years, Wal-Mart has been the largest company in the ...United States. Now, though, it is the largest company in the world. Its global labor practices and outsourcing strategies represent for many what contemporary economic globalization is all about. But Wal-Mart is not standing still, and is opening up stores everywhere. From Germany to Beijing to Mexico City to Tokyo, more than a billion shoppers can now hunt for bargains at a Wal-Mart superstore. Wal-Mart World is the first book to look at this incredibly important phenomenon in global perspective, with chapters that range from its growth in the US and impact on labor relations here to its fortunes overseas. How Wal-Mart manages this transition in the near future will play a significant role in the determining the character of the global economy. Wal-Mart World's impressively broad scope makes it necessary reading for anyone interested in the global impact of this economic colossus.
Cholesterol clearly plays an influential role in promoting the production of amyloid beta (Abeta) and possibly the progression of Alzheimer's Disease (AD). The AD Cholesterol-Lowering Treatment trial ...(ADCLT; 1 year duration) tested atorvastatin and found significant benefit on measures of cognition and depressive symptoms in treated patients (N = 32) compared to placebo (N = 31). We assessed the circulating levels of Abeta(1-40), Abeta(1-42), ceruloplasmin (copper chaperone), apolipoprotein E and HDL-cholesterol in blood collected at each clinical visit during the ADCLT. We also determined the circulating cholesterol, ceruloplasmin, and Abeta levels in AD and MCI (mild cognitive impairment) patients, and controls (two groups stratified by function; high and low) participating in our Brain Bank Program. Each Brain Bank individual was clinically assessed for performance on the Mini-Mental Status Exam (MMSE), Rey auditory verbal learning test (AVLT), Clock draw, and UPSIT (smell identification test). Among individuals of equal age and education, scores on the MMSE were significantly reduced in AD compared to both MCI and controls, as were scores on the UPSIT. Ability on delayed verbal recall was significantly reduced in AD compared to MCI, and in MCI compared to both control groups. Performance on the Clock draw was similar for AD and MCI patients, but was significantly reduced when comparing MCI to control. Both cholesterol and ceruloplasmin levels were significantly increased in low-function controls compared to the high-function control group, but were not different from levels identified in the MCI and AD patients. Significantly increased levels of Abeta(1-40) occurred in low- compared to high-function controls, with a further significant increase in MCI compared to low-function controls. Circulating Abeta(1-40) levels were decreased in AD compared to MCI. Levels of Abeta(1-42) were not significantly different between the groups. The slight gradual increase in circulating Abeta(1-40) and Abeta(1-42) levels produced by atorvastatin treatment in the ADCLT were not significant compared placebo. There was a trend for significant reduction in circulating ceruloplasmin levels after a year of atorvastatin therapy compared to levels observed at screen. The levels of HDL-cholesterol remained stable in the atorvastatin treated AD patients for 9 months and then decreased significantly compared to the placebo group at the 1-year time-point. The combined data support a role for cholesterol in AD and a possible influence of increasing circulating copper levels. The deterioration of function in controls and transition to MCI may be associated with concomitant incremental increases in circulating Abeta(1-40) levels. Increased cholesterol and ceruloplasmin levels may be associated with slight deterioration in function among controls as a precursor to impairment considered MCI. The clinical benefit of atorvastatin therapy is clearly not associated with decreased circulating Abeta or increased HDL-cholesterol, but a positive influence of reduced copper (ceruloplasmin) levels may be a consideration.
