A novel class of inhibitors that disrupts the stability of integrin heterodimers identified by CRISPR-tiling-instructed genetic screens.

The plasma membrane is enriched for receptors and signaling proteins that are accessible from the extracellular space for pharmacological intervention. Here we conducted a series of CRISPR screens using human cell surface proteome and integrin family libraries in multiple cancer models. Our results identified ITGAV (integrin αV) and its heterodimer partner ITGB5 (integrin ß5) as the essential integrin α/ß pair for cancer cell expansion. High-density CRISPR gene tiling further pinpointed the integral pocket within the ß-propeller domain of ITGAV for integrin αVß5 dimerization. Combined with in silico compound docking, we developed a CRISPR-Tiling-Instructed Computer-Aided (CRISPR-TICA) pipeline for drug discovery and identified Cpd_AV2 as a lead inhibitor targeting the ß-propeller central pocket of ITGAV. Cpd_AV2 treatment led to rapid uncoupling of integrin αVß5 and cellular apoptosis, providing a unique class of therapeutic action that eliminates the integrin signaling via heterodimer dissociation. We also foresee the CRISPR-TICA approach to be an accessible method for future drug discovery studies.

Grounded Theory Approach to Understand Self-Management of Opioid Recovery Through Pregnancy and Early Parenting.

OBJECTIVE: To develop a theory to explain the processes women use to self-manage recovery from opioid use disorder during pregnancy, the postpartum period, and early parenting. DESIGN: Constructivist grounded theory approach. PARTICIPANTS: Women (N = 16) who gave birth during the past 12 months and used medication for opioid use disorder for recovery through pregnancy and the postpartum period. METHODS: We recruited participants through seven medication-assisted treatment clinics in a mid-size Midwestern city and the surrounding suburbs and through online parenting and recovery community groups with national-based memberships. We conducted semistructured, individual audio interviews from November 2020 to July 2021. Interviews continued until we reached theoretical and meaning saturation. We used constant comparative methods during initial and intermediate coding. RESULTS: Participants described a central process, Growing as a Healthy Dyad, that included six processes they used to self-manage recovery: Maintaining Vigilance, Performing Self-Care, Putting in the Work of Recovery, Advocating, Navigating Social Support, and Acquiring Skills and Knowledge. These processes were affected by personal and social contextual factors. CONCLUSIONS: The grounded theory, Self-Management of Opioid Recovery Through Pregnancy and Early Parenting, can be used to explain the unique processes of self-management by women in opioid recovery and highlights the need for a strengths-based approach to caring for the maternal-infant dyad.

Engagement in Online Communities by New Mothers in Recovery from Opioid Use Disorder.

PURPOSE: The purpose of this study was to examine the role of engagement with online communities by women using medication-assisted treatment (MAT) to manage recovery from opioid use disorder (OUD) during pregnancy and the first year after birth. STUDY DESIGN AND METHODS: Ten participants were identified through purposive sampling for this secondary data analysis as part of a larger grounded theory study about ways women using MAT for recovery from OUD meet the needs of their mother-infant dyad. Inclusion criteria included: English-speaking, 18 years of age or older, living in the United States, within the first year after birth, using MAT to manage OUD, and identified engaging with online communities during pregnancy and/or postpartum. A categorical-content narrative approach was used. RESULTS: Three narratives were identified from the analysis, belonging , collaboration , and expecting success . CLINICAL IMPLICATIONS: Engagement in online communities can be a meaningful adjunct or replacement for in-person support. Online spaces are available 24/7 and allow people to join a community where they will not experience stigma and can find support tailored to their needs. Health care providers could extend their care for mothers affected by OUD by referring them to online communities for support of recovery self-management efforts.