Tigilanol tiglate is an oncolytic small molecule that induces immunogenic cell death and enhances the response of both target and non-injected tumors to immune checkpoint blockade.

BACKGROUND: Tigilanol tiglate (TT) is a protein kinase C (PKC)/C1 domain activator currently being developed as an intralesional agent for the treatment of various (sub)cutaneous malignancies. Previous work has shown that intratumoral (I.T.) injection of TT causes vascular disruption with concomitant tumor ablation in several preclinical models of cancer, in addition to various (sub)cutaneous tumors presenting in the veterinary clinic. TT has completed Phase I dose escalation trials, with some patients showing signs of abscopal effects. However, the exact molecular details underpinning its mechanism of action (MoA), together with its immunotherapeutic potential in oncology remain unclear. METHODS: A combination of microscopy, luciferase assays, immunofluorescence, immunoblotting, subcellular fractionation, intracellular ATP assays, phagocytosis assays and mixed lymphocyte reactions were used to probe the MoA of TT in vitro. In vivo studies with TT used MM649 xenograft, CT-26 and immune checkpoint inhibitor refractory B16-F10-OVA tumor bearing mice, the latter with or without anti-programmed cell death 1 (PD-1)/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mAb treatment. The effect of TT at injected and non-injected tumors was also assessed. RESULTS: Here, we show that TT induces the death of endothelial and cancer cells at therapeutically relevant concentrations via a caspase/gasdermin E-dependent pyroptopic pathway. At therapeutic doses, our data demonstrate that TT acts as a lipotoxin, binding to and promoting mitochondrial/endoplasmic reticulum (ER) dysfunction (leading to unfolded protein responsemt/ER upregulation) with subsequent ATP depletion, organelle swelling, caspase activation, gasdermin E cleavage and induction of terminal necrosis. Consistent with binding to ER membranes, we found that TT treatment promoted activation of the integrated stress response together with the release/externalization of damage-associated molecular patterns (HMGB1, ATP, calreticulin) from cancer cells in vitro and in vivo, characteristics indicative of immunogenic cell death (ICD). Confirmation of ICD in vivo was obtained through vaccination and rechallenge experiments using CT-26 colon carcinoma tumor bearing mice. Furthermore, TT also reduced tumor volume, induced immune cell infiltration, as well as improved survival in B16-F10-OVA tumor bearing mice when combined with immune checkpoint blockade. CONCLUSIONS: These data demonstrate that TT is an oncolytic small molecule with multiple targets and confirms that cell death induced by this compound has the potential to augment antitumor responses to immunotherapy.

Cultivating Native American scientists: an application of an Indigenous model to an undergraduate research experience.

With growing evidence demonstrating the impact of undergraduate research experiences on educational persistence, efforts are currently being made to expand these opportunities within universities and research institutions throughout the United States. Recruiting underrepresented students into these programs has become an increasingly popular method of promoting diversity in science. Given the low matriculation into postsecondary education and completion rates among Native Americans, there is a great need for Native American undergraduate research internships. Although research has shown that Western education models tend to be less effective with Native populations, the implementation of indigenous epistemologies and pedagogies within higher education, including research experiences, is rare. This study explores the applicability of a cognitive apprenticeship merged with an indigenous approach, the Circle of Courage, to build a scientific learning environment and enhance the academic and professional development of Native students engaged in an undergraduate research experience in the health sciences. Data were drawn from focus groups with 20 students who participated in this program in 2012-2014. Questions explored the extent to which relational bonds between students and mentors were cultivated as well as the impact of this experience on the development of research skills, intellectual growth, academic and professional self-determination, and the attachment of meaning to their research experiences. Data were analyzed via deductive content analysis, allowing for an assessment of how the theoretical constructs inherent to this model (belonging, mastery, independence, and generosity) impacted students. Findings suggest that engaging Native students in research experiences that prioritize the needs of belonging, mastery, independence, and generosity can be a successful means of fostering a positive learning environment, in which students felt like significant members of a research team, developed a greater understanding and appreciation for the role of science in education and its various applications to socially relevant health issues, made more informed decisions about a career in research and the health sciences, and worked toward improving the health and well-being of others while also inspiring hope among their people back home. This study represents an extension of the application of the Circle of Courage to an undergraduate research experience and provides evidence of its ability to be used as a framework for cultivating Native scientists.

My Journey: Development and Practice-Based Evidence of a Culturally Attuned Teen Pregnancy Prevention Program for Native Youth.

A clear need exists for teen pregnancy prevention programs that are responsive to the specific needs and cultural contexts of Native American communities. Recent data indicates that the birth rate for Native teens is nearly two and a half times the rate for White teens (32.9 versus 13.2). To address this disparity, we conducted formative research with Northern Plains Native American community members, resulting in My Journey, a culturally attuned curriculum for 6⁻8th graders. My Journey is grounded in traditional values and teachings to promote self-efficacy in sexual health decision-making and engagement in prosocial behaviors. We conducted a pilot study with 6⁻8th grade students (n = 45), aged 11⁻14 years (22 females, 23 males). Pilot study findings confirm program feasibility and acceptability. The process evaluation revealed that teachers liked the curriculum, particularly its adaptability of cultural components and ease of student engagement. The outcome evaluation demonstrated that My Journey provided an avenue for NA youth to increase their sex refusal self-efficacy. Application of the culture cube framework revealed My Journey has made a meaningful practice-based evidence contribution as a community-defined, culturally integrated curriculum that is effective. Future directions include broader implementation of My Journey, including adaption for additional populations.

Cultural and Social Predictors of Substance Abuse Recovery among American Indian and Non-American Indian Pregnant and Parenting Women.

Substance abuse is especially undesirable among pregnant or parenting women (PPW). As such, there is a need to examine the factors impacting positive treatment outcomes, particularly among American Indian/Alaska Native (AI/AN) PPW, as they are seeking substance abuse treatment at rates considerably higher than the national average. This study aimed to identify the social and cultural mechanisms that support their recovery. Qualitative analyses were used to identify mechanisms used by AI and non-AI PPW in their recovery. Several differences between AI and non-AI PPW emerged. AI participants mentioned their families more often as the reason why they wanted to become or stay sober. In addition to familial support, AI participants relied on a variety of other sources for assistance in their recovery. Many of the women had difficulty defining specific aspects of their culture, especially in relation to their recovery. However, for AI PPW, many aspects of AI culture were identified as they described their recovery, suggesting the often subtle ways culture can impact everyday life. Our findings indicated that women utilized cultural supports in different ways; therefore, it is necessary to help them define their culture in ways that are meaningful in their recovery.

A research experience for American Indian undergraduates: Utilizing an actor-partner interdependence model to examine the student-mentor dyad.

The majority of research examining Undergraduate Research Experiences focuses singularly on student-reported outcomes, often overlooking assessment of the mentor role in student learning and outcomes following these experiences. The goal of the current study was to examine the student-mentor dyad at the beginning and end of a 10-week summer research experience for American Indian undergraduates utilizing a series of actor-partner interdependence models within SEM. Participants included 26 undergraduate interns (50% American Indian; 50% American Indian and White; M age = 24) and 27 mentors (89% White; M age = 47). Findings indicated that in accounting for all potential paths between students and mentors, the partner path between mentor beliefs at the beginning of the program and students' skills related to autonomy (ß =.59, p = .01) and academic resilience (ß =.44, p = .03) at the end of the program were significant. These findings suggest the important impact of mentor beliefs on student outcomes, a relationship that should be adequately assessed and continue to be important focus of undergraduate research experiences. Findings further indicate the important role of mentors for American Indian undergraduates.

Applying the Theory of Reasoned Action to Understanding Teen Pregnancy with American Indian Communities.

Objectives American Indian girls have higher teen pregnancy rates than the national rate. Intervention studies that utilize the Theory of Reasoned Action have found that changing attitudes and subjective norms often leads to subsequent change in a variety of health behaviors in young adults. The current study goal is to better understand sexual decision-making among American Indian youth using the Theory of Reasoned Action model and to introduce ways to utilize attitudes and subjective norms to modify risky behaviors. Methods The project collected qualitative data at a reservation site and an urban site through 16 focus groups with American Indian young people aged 16-24. Results Attitudes towards, perceived impact of, and perception of how others felt about teen pregnancy vary between American Indian parents and non-parents. Particularly, young American Indian parents felt more negatively about teen pregnancy. Participants also perceived a larger impact on female than male teen parents. Conclusions There are differences between American Indian parents and non-parents regarding attitudes towards, the perceived impact of, and how they perceived others felt about teen pregnancy. Teen pregnancy prevention programs for American Indian youth should include youth parents in curriculum creation and curriculum that addresses normative beliefs about teen pregnancy and provides education on the ramifications of teen pregnancy to change attitudes.

Identifying sexual health protective factors among Northern Plains American Indian youth: An ecological approach utilizing multiple perspectives.

This study examined aspects of the sociocultural context in which American Indian (AI) teen pregnancy occurs, focusing specifically on protective factors for Northern Plains AI youth. Principles of community-based participatory research guided the qualitative data collection from 185 community members (focus groups with AI youth, youth parents, and elders; interviews with health care providers and school personnel) from a reservation and an urban community. Results indicated three protective systems impacted the sexual health and behaviors of AI youth: school, family, and enculturation. These findings provide a better understanding of how specific protective factors within these systems may buffer AI youth from involvement in risky sexual behaviors and work to inform culturally relevant prevention and intervention efforts.

Teen Pregnancy Prevention Program Recommendations from Urban and Reservation Northern Plains American Indian Community Members.

Despite declines over the past few decades, the United States has one of the highest rates of teen pregnancy compared to other industrialized nations. American Indian youth have experienced higher rates of teen pregnancy compared to the overall population for decades. Although it's known that community and cultural adaptation enhance program effectiveness, few teen pregnancy prevention programs have published on recommendations for adapting these programs to address the specific needs of Northern Plains American Indian youth. We employed a mixed-methods analysis of 24 focus groups and 20 interviews with a combined total of 185 urban and reservation-based American Indian youth and elders, local health care providers, and local school personnel to detail recommendations for the cultural adaptation, content, and implementation of a teen pregnancy prevention program specific to this population. Gender differences and urban /reservation site differences in the types of recommendations offered and the potential reasons for these differences are discussed.

Understanding gender roles in teen pregnancy prevention among American Indian youth.

OBJECTIVES: To examine the impact of gender norms on American Indian (AI) adolescents' sexual health behavior. METHODS: The project collected qualitative data at a reservation site and an urban site through 24 focus groups and 20 key informant interviews. RESULTS: The reasons that AI youth choose to abstain or engage in sexual intercourse and utilize contraception vary based on gender ideologies defined by the adolescent's environment. These include social expectations from family and peers, defined roles within relationships, and gender empowerment gaps. CONCLUSIONS: Gender ideology plays a large role in decisions about contraception and sexual activity for AI adolescents, and it is vital to include redefinitions of gender norms within AI teen pregnancy prevention program.

Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen receptor-positive patients.

PURPOSE: To evaluate the efficacy of the aromatase inhibitor letrozole in preselected estrogen receptor (ER)-positive relapsed epithelial ovarian cancer patients and to identify markers that predict endocrine-sensitive disease. EXPERIMENTAL DESIGN: This was a phase II study of letrozole 2.5 mg daily until clinical or marker evidence of disease progression in previously treated ER-positive ovarian cancer patients with a rising CA125 that had progressed according to Rustin's criteria. The primary end point was response according to CA125 and response evaluation criteria in solid tumors (RECIST) criteria. Marker expression was measured by semiquantitative immunohistochemistry in sections from the primary tumor. RESULTS: Of 42 patients evaluable for CA125 response, 7 (17%) had a response (decrease of >50%), and 11 (26%) patients had not progressed (doubling of CA125) following 6 months on treatment. The median time taken to achieve the CA125 nadir was 13 weeks (range 10-36). Of 33 patients evaluable for radiological response, 3 (9%) had a partial remission, and 14 (42%) had stable disease at 12 weeks. Eleven patients (26%) had a PFS of >6 months. Subgroup analysis according to ER revealed CA125 response rates of 0% (immunoscore, 150-199), 12% (200-249), and 33% (250-300); P = 0.028, chi(2) for trend. Expression levels of HER2, insulin-like growth factor binding protein 5, trefoil factor 1, and vimentin were associated with CA125 changes on treatment. CONCLUSIONS: This is the first study of a hormonal agent in a preselected group of ER-positive ovarian cancer patients. A signature of predictive markers, including low HER2 expression, predicts response.