NQO1-dependent, tumor-selective radiosensitization of non-small cell lung cancers

Purpose: Development of tumor-specific therapies for the treatment of recalcitrant non-small cell lung cancers (NSCLCs) are urgently needed. Here, we investigated the ability of ß-lapachone (ß-lap, ARQ761 in clinical form) to selectively potentiate the effects of ionizing radiation (IR, 1–3 Gy) in NSCLCs that over-express NAD(P)H:Quinone Oxidoreductase 1 (NQO1). Experimental Design: The mechanism of lethality of low dose IR in combination with sublethal doses of ß-lap were evaluated in NSCLC lines in vitro and validated in subcutaneous and orthotopic xenograph models in vivo. Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus co-treatments were performed to validate therapeutic efficacy and mechanism of action. Results: ß-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD+/ATP levels, and increased DSB lesions over time in vitro. Radiosensitization of orthotopic, as well as subcutaneous, NSCLCs occurred with high apparent cures (>70%), even though 1/8 ß-lap doses reach subcutaneous versus orthotopic tumors. No methemoglobinemia or long-term toxicities were noted in any normal tissues, including mouse liver that expresses the highest level of NQO1 (~12 Units) of any normal tissue. PK/PD responses confirm that IR + ß-lap treatments hyperactivate PARP activity, greatly lower NAD+/ATP levels and dramatically inhibit DSB repair in exposed NQO1+ cancer tissue, while low NQO1 levels and high levels of Catalase in associated normal tissue were protective. Conclusion: Our data suggest that combination of sublethal doses of ß-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + ß-lapachone against patients with NQO1+ NSCLCs

Cost-effectiveness of a chronic pain intervention for people living with HIV (PLWH)

Background: Chronic pain is a common, disabling, and costly comorbidity, particularly in people living with HIV (PLWH). This study developed and pilot tested a pain self-management intervention for chronic pain tailored to PLWH called Skills TO Manage Pain (STOMP). Objectives: Given the additional resources needed to deliver STOMP in HIV clinical settings, an important objective of the pilot study was to assess not only STOMP’s preliminary efficacy, but also its cost-effectiveness. Research design and subjects: The present study draws from a 44-participant, 2-arm randomized pilot trial of the STOMP intervention vs usual care among PLWH and at least moderate chronic pain (Clinicaltrials.gov: NCT02824562). Cost-effectiveness is presented as the incremental cost-effectiveness ratio (ICER). Costs were considered from the clinic perspective over a 1-year time horizon using real costs from the pilot trial. It was conservatively assumed there would be no costs savings. The Standard Gamble (SG) method was used to directly measure utilities. Results: Thirty-six participants met inclusion criteria for the present analyses. Mean age was 52 years; 61% were female and 86% were black. The total cost of STOMP was $483.83 per person. Using the SG method, the change in QALYs was 0.15, corresponding to an ICER of$3,225. Conclusions: STOMP’s cost/QALY is substantially lower than the $50,000 to$100,000/QALY benchmark often used to indicate cost-effectiveness. Although based on a pilot trial and, therefore, preliminary, these findings are promising, and suggest the importance of cost analyses in future STOMP trials

Rationale and study protocol for Unidas por la Vida (United for Life): A dyadic weight-loss intervention for high-risk Latina mothers and their adult daughters.

BackgroundHalf of Mexican-American women are under-active and nearly 78% are overweight/obese. The high lifetime risk of developing type 2 diabetes necessitates a culturally appropriate lifestyle intervention.PurposeUnidas por la Vida is a novel dyadic intervention that capitalizes on the centrality of family in Latino culture to mobilize an existing family dyad as a resource for health behavior change. The intervention aims to improve health behaviors and promote weight loss in two at-risk members of the same family: mothers with type 2 diabetes and their overweight/obese adult daughters who are at risk for developing diabetes.MethodsParticipants (N = 460 mother-adult daughter dyads) will be randomized into one of three conditions: 1) dyadic participation (mothers-daughters) in a lifestyle intervention; 2) individual participation (mothers alone; unrelated daughters alone) in a lifestyle intervention; and 3) mother-daughter dyads in a minimal intervention control group.ResultsThe primary outcome is weight loss. Secondary outcomes include physical activity, dietary intake, physiological measures (e.g. HbA1c), and body composition. Both the dyadic and individual interventions are expected to produce greater weight loss at 6, 12, and 18 months than those in minimal intervention control group, with women assigned to the dyadic intervention expected to lose more weight and to maintain the weight loss longer than women assigned to the individual intervention.ConclusionBecause health risks are often shared by multiple members of at-risk families, culturally appropriate, dyadic interventions have the potential to increase the success of behavior change efforts and to extend their reach to multiple family members.Trial registrationClinicalTrials.gov identifier NCT02741037

Evaluation of the anti-tumor effects of lactate dehydrogenase inhibitor galloflavin in endometrial cancer cells

High rates of aerobic glycolysis represent a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. The present study was aimed at evaluating the potential of a novel lactate dehydrogenase (LDH) inhibitor, Galloflavin, as a therapeutic agent for endometrial cancer. Our results revealed that Galloflavin effectively inhibited cell growth in endometrial cancer cell lines and primary cultures of human endometrial cancer through its involvement in multiple signaling pathways that regulate metabolism, cell cycle, apoptosis, cell stress and metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0097-x) contains supplementary material, which is available to authorized users

Benevolent failures : the economics of philanthropy in Victorian literature

textThis dissertation critically examines why mid-Victorian fiction often dismisses or complicates monetary transactions and monetary charity, even as it negatively portrays differences in social status and wealth. I argue that the novel uses representations of failed charity to reconstruct, however briefly, a non- monetary and non-economic source of value. Further, I examine how the novel uses techniques of both genre and style to predict, form, and critique alternate, non-economic, social models. While tension surrounding the practice of charity arises in the late eighteenth century, the increasing dominance of political economy in public discourse forced Victorian literature to take a strong stance, for reasons of both ethics and genre. This stance is complicated by the eighteenth-century legacy that sees charity as a kind of luxury. If giving to the poor makes us feel good, this logic suggests, surely it isn’t moral. Thus, while much eighteenth- and nineteenth-century literature remains dedicated to the ethics of charity, the practice becomes immensely complex. By discussing the works of Tobias Smollett, Charles Dickens, Elizabeth Barrett Browning, and George Eliot, this project exposes a wide variety of responses to this deep cultural anxiety. These authors are, ultimately, strongly invested in redefining the meaning of benevolence as a valid form of social action by moving that benevolence away from monetary gifts and toward abstractly correct moral feelings, though their individual solutions vary widely.Englis

Triple, Mutually Orthogonal Cycloadditions Through the Design of Electronically Activated SNO-OCTs

Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design of new compounds capable of fast and predictable reactions. The ability to easily modify heterocyclic strained cyclooctynes containing sulfamate backbones (SNO-OCTs) enables electronic tuning of the relative rates of reactions of SNO-OCTs in cycloadditions with Type I–III dipoles. As opposed to optimizations based on just one specific dipole class, the electrophilicity of the alkynes in SNO-OCTs can be manipulated to achieve divergent reactivities and furnish mutually orthogonal dual ligation systems. Significant rate enhancements for reactions of a difluorinated SNO-OCT derivative compared to the parent scaffold were noted, with the second-order rate constant in cycloadditions with diazoacetamides exceeding 1 M−1 s −1 . Computational and experimental studies were employed to inform the design of triple ligation systems that encompass three orthogonal reactivities. Finally, polar SNO-OCTs are rapidly internalized by mammalian cells and remain functional in the cytosol for live-cell labeling, highlighting their potential for diverse in vitro and in vivo applications

Triple, Mutually Orthogonal Bioorthogonal Pairs through the Design of Electronically Activated Sulfamate-Containing Cycloalkynes

© Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design of new compounds that are capable of fast and predictable reactions. The ability to easily modify S-, N-, and O-containing cyclooctynes (SNO-OCTs) enables electronic tuning of various SNO-OCTs to influence their cycloaddition rates with Type I-III dipoles. As opposed to optimizations based on just one specific dipole class, the electrophilicity of the alkynes in SNO-OCTs can be manipulated to achieve divergent reactivities and furnish mutually orthogonal dual ligation systems. Significant reaction rate enhancements of a difluorinated SNO-OCT derivative, as compared to the parent scaffold, were noted, with the second-order rate constant in cycloadditions with diazoacetamides exceeding 5.13 M-1 s-1. Computational and experimental studies were employed to inform the design of triple ligation systems that encompass three orthogonal reactivities. Finally, polar SNO-OCTs are rapidly internalized by mammalian cells and remain functional in the cytosol for live-cell labeling, highlighting their potential for diverse in vitro and in vivo applications

Polymer Microparticles Prolong Delivery of the 15-PGDH Inhibitor SW033291

As the prevalence of age-related fibrotic diseases continues to increase, novel antifibrotic therapies are emerging to address clinical needs. However, many novel therapeutics for managing chronic fibrosis are small-molecule drugs that require frequent dosing to attain effective concentrations. Although bolus parenteral administrations have become standard clinical practice, an extended delivery platform would achieve steady-state concentrations over a longer time period with fewer administrations. This study lays the foundation for the development of a sustained release platform for the delivery of (+)SW033291, a potent, small-molecule inhibitor of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enzyme, which has previously demonstrated efficacy in a murine model of pulmonary fibrosis. Herein, we leverage fine-tuned cyclodextrin microparticles—specifically, β-CD microparticles (β-CD MPs)—to extend the delivery of the 15-PGDH inhibitor, (+)SW033291, to over one week

Rationale and study protocol for Unidas por la Vida (United for Life): A dyadic weight-loss intervention for high-risk Latina mothers and their adult daughters.

BackgroundHalf of Mexican-American women are under-active and nearly 78% are overweight/obese. The high lifetime risk of developing type 2 diabetes necessitates a culturally appropriate lifestyle intervention.PurposeUnidas por la Vida is a novel dyadic intervention that capitalizes on the centrality of family in Latino culture to mobilize an existing family dyad as a resource for health behavior change. The intervention aims to improve health behaviors and promote weight loss in two at-risk members of the same family: mothers with type 2 diabetes and their overweight/obese adult daughters who are at risk for developing diabetes.MethodsParticipants (N = 460 mother-adult daughter dyads) will be randomized into one of three conditions: 1) dyadic participation (mothers-daughters) in a lifestyle intervention; 2) individual participation (mothers alone; unrelated daughters alone) in a lifestyle intervention; and 3) mother-daughter dyads in a minimal intervention control group.ResultsThe primary outcome is weight loss. Secondary outcomes include physical activity, dietary intake, physiological measures (e.g. HbA1c), and body composition. Both the dyadic and individual interventions are expected to produce greater weight loss at 6, 12, and 18 months than those in minimal intervention control group, with women assigned to the dyadic intervention expected to lose more weight and to maintain the weight loss longer than women assigned to the individual intervention.ConclusionBecause health risks are often shared by multiple members of at-risk families, culturally appropriate, dyadic interventions have the potential to increase the success of behavior change efforts and to extend their reach to multiple family members.Trial registrationClinicalTrials.gov identifier NCT02741037

Intervention Mapping to develop a Social Cognitive Theory-based intervention for chronic pain tailored to individuals with HIV

Chronic pain is an important comorbidity among individuals with HIV. Behavioral interventions are widely regarded as evidence-based, efficacious non-pharmacologic interventions for chronic pain in the general population. An accepted principle in behavioral science is that theory-based, systematically-developed behavioral interventions tailored to the unique needs of a target population are most likely to be efficacious. Our aim was to use Intervention Mapping to systematically develop a Social Cognitive Theory (SCT)-based intervention for chronic pain tailored to individuals with HIV that will improve pain intensity and pain-related functional impairment. Our Intervention Mapping process was informed by qualitative inquiry of 24 patients and seven providers in an HIV primary care clinic. The resulting intervention includes group and one-on-one sessions and peer and staff interventionists. We also developed a conceptual framework that integrates our qualitative findings with SCT-based theoretical constructs. Using this conceptual framework as a guide, our future work will investigate the intervention's impact on chronic pain outcomes, as well as our hypothesized proximal mediators of the intervention's effect. Keywords: Chronic pain, HIV, Intervention mapping, Intervention development, Social cognitive theor