HER3 V104 mutations regulate cell signaling, growth, and drug sensitivity in cancer.

HER3 is mutated in ~2%-10% of cancers depending on the cancer type. We found the HER3-V104L mutation to be activating from patient-derived mutations introduced via lentiviral transduction in HER3KO HER2 + HCC1569 breast cancer cells in which endogenous HER3 was eliminated by CRISPR/Cas9. Cells expressing HER3-V104L showed higher p-HER3 and p-ERK1/2 expression versus cells expressing wild-type HER3 or HER3-V104M.

Metabolic complications in lung transplantation for cystic fibrosis - A case control study.

Background: Metabolic complications post-lung transplant are poorly understood and little is known about how these complications differ between patients with or without cystic fibrosis (pwCF and pwoCF). This study compared post-lung transplant outcomes between pwCF and pwoCF relating to survival and incidence of diabetes, dyslipidaemia, hypertension, and renal impairment.

Methods: A retrospective (2004-2017) case-control study involving 90 pwCF and 90 pwoCF (age, sex and year of transplant matched) was conducted.

Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer.

Unlabelled: HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKI) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2.

HER2 inhibition increases non-muscle myosin IIA to promote tumorigenesis in HER2+ breast cancers.

HER2 is over-expressed in around 15% to 20% of breast cancers. HER3 plays a critical role in HER2 mediated tumorigenesis. Increased HER3 transcription and protein levels occur upon inhibition of HER2.

RIDR-PI-103, ROS-activated prodrug PI3K inhibitor inhibits cell growth and impairs the PI3K/Akt pathway in BRAF and MEK inhibitor-resistant BRAF-mutant melanoma cells.

Reactive oxygen species (ROS) levels are elevated after acquisition of resistance to v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors including dabrafenib and MEK inhibitors such as trametinib in BRAF-mutant melanoma. To circumvent toxicity to PI-103 (a pan PI3K inhibitor), we utilized a novel ROS-induced drug release (RIDR)-PI-103, with a self-cyclizing moiety linked to PI-103. Under high ROS conditions, RIDR-PI-103 releases PI-103, which inhibits conversion of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) to phosphatidylinositol 3,4,5-triphosphate (PIP 3 ).

HER3 Alterations in Cancer and Potential Clinical Implications.

In recent years, the third member of the HER family, kinase impaired HER3, has become a target of interest in cancer as there is accumulating evidence that HER3 plays a role in tumor growth and progression. This review focuses on HER3 activation in bladder, breast, colorectal, and lung cancer disease progression. HER3 mutations occur at a rate up to ~10% of tumors dependent on the tumor type.

Feasibility and Acceptability of Virtual Implementation of a Sexual Reproductive Health Teen Pregnancy Prevention Program for Native Youth.

American Indian/Alaska Native (Native) youth face high rates of substance use, teen pregnancy and sexually transmitted infections. In response to the COVID-19 pandemic, Respecting the Circle of Life (RCL), a sexual reproductive health and teen pregnancy prevention program for Native youth and their trusted adult, was adapted and delivered in a virtual format with Native youth in a rural, reservation-based Native community. This manuscript describes the adaptation process, feasibility, and acceptability of virtual program implementation.

Improving communication between American Indian youth and caregivers to prevent teenage pregnancy.

American Indian (AI) youth are at increased risk for poor reproductive health outcomes. Parental communication and monitoring are established predictors of sexual risk-taking among adolescents. No program evaluations of sexual risk avoidance programs have focused exclusively on AI youth and parents.

Azhe'é Bidziil (Strong Fathers): Study Protocol for the Pilot Evaluation of an American Indian Fatherhood Program to Improve the Health and Wellbeing of Diné (Navajo) Fathers.

Introduction: Considering the critical role that American Indian and Alaska Native (Native) men play in family and child health, there is an urgent need to collaborate with Native communities in developing interventions and policies to improve Native men's health status. This study aims to address a significant gap in research by designing and implementing a culturally grounded health promotion program to increase economic stability, promote positive parenting, and build healthy relationships among Native fathers. The Azhe'é Bidziil ("Strong Fathers") study protocol, developed in response to community advisory board feedback, illustrates a community-engaged approach to developing and implementing a fatherhood program in two Diné (Navajo) communities.

IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma.

The use of BRAF and MEK inhibitors for patients with BRAF-mutant melanoma is limited as patients relapse on treatment as quickly as 6 months due to acquired resistance. We generated trametinib and dabrafenib resistant melanoma (TDR) cell lines to the MEK and BRAF inhibitors, respectively. TDR cells exhibited increased viability and maintenance of downstream p-ERK and p-Akt as compared to parental cells.

The impact of biosimilar insulins on the diabetes landscape.

The cost of diabetes care in the United States continues to rise, with insulin costs growing rapidly. Accessibility and affordability of these life-saving medications are concerns for providers and patients that need to be addressed. Availability of biosimilar insulin products may help address these issues by introducing additional competition to the insulin market, but they may also face adoption challenges from patients and health care providers alike.

Diné (Navajo) female perspectives on mother-daughter communication and cultural assets around the transition to womanhood: a cross-sectional survey.

Background: The inclusion of protective factors ("assets") are increasingly supported in developing culturally grounded interventions for American Indian (AI) populations. This study sought to explore AI women's cultural assets, perspectives, and teachings to inform the development of a culturally grounded, intergenerational intervention to prevent substance abuse and teenage pregnancy among AI females.

Methods: Adult self-identified AI women (N = 201) who reside on the Navajo Nation completed a cross-sectional survey between May and October 2018.

Impacts of the respecting the circle of life teen pregnancy prevention program on risk and protective factors for early substance use among native American youth.

Background: Early substance use disproportionately impacts Native American (Native) youth and increases their risk for future abuse and dependence. The literature urges for interventions to move beyond focusing on single risk behaviors (e.g.

Prevention of Sexually Transmitted Diseases and Pregnancy Prevention Among Native American Youths: A Randomized Controlled Trial, 2016-2018.

To evaluate the efficacy of the Respecting the Circle of Life program (RCL) among Native American youths 11 to 19 years of age residing in a rural reservation community in the southwestern United States. Between 2016 and 2018, we conducted a randomized controlled trial of the RCL program with 534 Native youths. Participants completed assessments at baseline and 9 and 12 months after the intervention.

Rigorous evaluation of a substance use and teen pregnancy prevention program for American Indian girls and their female caregivers: a study protocol for a randomized controlled trial.

Background: Early sexual initiation is associated with higher risk for sexually transmitted infection, teen pregnancy, domestic violence and substance use in later adolescence and early adulthood. Native American adolescents are more likely to have early sexual initiation compared to other racial/ethnic groups. Few programs designed with and for Native adolescents to delay sexual initiation and substance use have been tested through rigorous evaluations.

Feasibility, Acceptability, and Preliminary Impact of Asdzáán Be'eená: An Intergenerational, Strength-Based, and Culturally Grounded Program to Improve the Health of Navajo Families.

Native American youth endure a complex interplay of factors that portend greater risk-taking behaviors and contribute to marked health disparities experienced in adolescence. The Asdzáán Be'eená ("Female Pathways" in Navajo) program was developed as a primary prevention program to prevent substance use and teen pregnancy among Navajo girls. The Asdzáán Be'eená program consists of 11 lessons delivered to dyads of girls ages 8 to 11 years and their female caregivers.

Empowering our people: Predictors of retention in an STI risk reduction program among rural Native Americans with binge substance use.

Purpose: Substance use and sexual risk-taking have been shown to co-occur. Programs focused on sexually transmitted infections (STIs) reduction may benefit substance-using, particularly binge substance-using, adults. This is especially true for rural Native American communities who endure sexual and substance use disparities and have few STI risk reduction programs.

PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects.

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies.

Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline Impairs PI3K Signaling, Increases DNA Damage Response and Reduces Breast Cancer Cell Growth.

RIDR-PI-103 is a novel reactive oxygen species (ROS)-induced drug release prodrug with a self-cyclizing moiety linked to a pan-PI3K inhibitor (PI-103). Under high ROS, PI-103 is released in a controlled manner to inhibit PI3K. The efficacy and bioavailability of RIDR-PI-103 in breast cancer remains unexplored.

BRAF Mutant Melanoma Adjusts to BRAF/MEK Inhibitors via Dependence on Increased Antioxidant SOD2 and Increased Reactive Oxygen Species Levels.

B-Rapidly Accelerated Fibrosarcoma (BRAF) mutations are found in about 50% of melanoma patients. Treatment with Food and Drug Administration (FDA)-approved BRAF and MAP/ERK kinase (MEK) inhibitors has improved progression free and overall survival of patients with BRAF mutant melanoma. However, all responders develop resistance typically within 1 year of treatment with these inhibitors.

Current Advances in the Treatment of BRAF-Mutant Melanoma.

Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15-20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly.

Protecting our future generation: study protocol for a randomized controlled trial evaluating a sexual health self-care intervention with Native American youth and young adults.

Background: Disparities in sexually transmitted infections (STI) are an urgent problem among Native American youth and young adults which are not fully explained by different sexual or related behaviors. These sexual health disparities are more likely attributed to social environments and structural determinants such as a shortage of sexual healthcare providers, lower socioeconomic status, and access barriers to STI screening and treatment, including geographic isolation and confidentiality concerns. Innovative, non-clinic based alternatives to promote STI screening and treatment are essential for alleviating these disparities.

Development of a Risk Score to Predict New Pacemaker Implantation After Transcatheter Aortic Valve Replacement.

Objectives: The aim of this study was to define risk factors and develop a predictive risk score for new pacemaker implantation (PMI) after transcatheter aortic valve replacement (TAVR).

Background: TAVR has become an accepted treatment alternative for patients with severe aortic stenosis at elevated surgical risk. New PMI is a common occurrence after TAVR and is associated with poorer outcomes.

Predictors of Responsiveness Among American Indian Adolescents to a Community-Based HIV-Risk Reduction Intervention Over 12 Months.

This analysis explored predictors of responsiveness to the Respecting the Circle of Life (RCL) intervention, a sexual and reproductive health program for American Indian (AI) youth. Data were collected over 12-month follow-up with 267 AI youth aged 13-19. We used mixed effects regression models to examine: (1) whether trajectory patterns of HIV/AIDS knowledge, condom beliefs, condom use self-efficacy, condom use intention and partner negotiation skills differed by baseline levels categorized into low, medium, and high scorers, and (2) the characteristics of youth who made no improvement over the post-intervention period.

Utilization of Reactive Oxygen Species Targeted Therapy to Prolong the Efficacy of BRAF Inhibitors in Melanoma.

BRAF mutations occur in about 50% of melanoma patients. FDA approved BRAF and MEK inhibitors have improved the prognosis of patients with BRAF mutations. However, all responders develop resistance typically within one year of treatment.