Proinsulin folding within the endoplasmic reticulum (ER) remains incompletely understood, but it is clear that in mutant INS gene–induced diabetes of youth (MIDY), progression of the (three) native disulfide bonds of proinsulin becomes derailed, causing insulin deficiency, β-cell ER stress, and onset of diabetes. Herein, we have undertaken a molecular dissection of proinsulin disulfide bond formation, using bioengineered proinsulins that can form only two (or even only one) of the native proinsulin disulfide bonds. In the absence of preexisting proinsulin disulfide pairing, Cys(B19)-Cys(A20) (a major determinant of ER stress response activation and proinsulin stability) preferentially initiates B-A chain disulfide bond formation, whereas Cys(B7)-Cys(A7) can initiate only under oxidizing conditions beyond that existing within the ER of β-cells. Interestingly, formation of these two “interchain” disulfide bonds demonstrates cooperativity, and together, they are sufficient to confer intracellular transport competence to proinsulin. The three most common proinsulin disulfide mispairings in the ER appear to involve Cys(A11)-Cys(A20), Cys(A7)-Cys(A20), and Cys(B19)-Cys(A11), each disrupting the critical Cys(B19)-Cys(A20) pairing. MIDY mutations inhibit Cys(B19)-Cys(A20) formation, but treatment to force oxidation of this disulfide bond improves folding and results in a small but detectable increase of proinsulin export. These data suggest possible therapeutic avenues to ameliorate ER stress and diabetes.

No abstract

Breast cancer is the most prevalent cancer affecting women globally and in Morocco, where more than one fourth of patients are diagnosed at advanced stages. This study aimed to investigate sociocultural barriers that contribute to delayed presentation and diagnosis of breast cancer among women in Marrakesh, Morocco. Qualitative interviews were conducted with 25 breast cancer patients who received care at the CHU Mohammed VI Hospital in Marrakesh to elicit barriers to diagnosis and treatment and ease of access to care. Interviews with breast cancer patients revealed several themes regarding structural and sociocultural barriers to initial diagnosis and treatment. Structural barriers included high treatment-associated costs for patients and their families, burden of transportation to central treatment centers, and limited access to appropriate health care resources. Sociocultural barriers included perceived attack on one's identity associated with breast cancer diagnosis and treatment, influence of the local community, and ideas of faith, spirituality, and conception of death. Findings from this study can help identify areas for improved access and education of patients in order to improve breast cancer diagnostic and treatment efforts and enhance opportunities for early detection.

No abstract

INTRODUCTION: To acquire in-depth understanding about patient preferences regarding the timing of long-acting reversible contraceptive (LARC) insertion after childbirth. METHODS: We conducted semi-structured interviews with pregnant women planning to use LARC postpartum (n=5). Participants watched a standardized video explaining LARC insertion timing options. Interviews were audio recorded, transcribed verbatim, and coded by two authors (AAS, MHM) using qualitative content analysis. RESULTS: Interviewees identified a variety of personal preferences for timing of LARC insertion. Cited reasons for preferring immediate postpartum insertion (n=3 women) included strong desire to prevent rapid repeat pregnancy, wanting to initiate contraception prior to being occupied with a new baby, and ability to address potential issues with their LARC device at the postpartum visit. Women (n=2) preferring outpatient insertion reported wanting to let the body recuperate after childbirth before initiating contraception and concern about expulsion and potential risks to breastfeeding with immediate insertion. Regardless of personal preferences for timing of insertion, all interviewees supported making immediate postpartum insertion available to women. Participants reported enthusiasm for discussing contraceptive options with any provider at any time during their prenatal care visits and expressed an affinity for receiving information via in-person conversations and visual formats (e.g. video, pamphlets) that could be shared with a partner. CONCLUSION: Our findings suggest that pregnant women have a range of preferences regarding timing of postpartum LARC insertion and support making immediate postpartum insertion available to women who desire it. Enhancing access to this service may align with women’s contraceptive preferences and enhance their ability to meet their reproductive goals.