Functional studies have shown that the oxygenation state of the erythrocyte regulates many important pathways, including glucose metabolism, membrane mechanical stability, and cellular adenosine triphosphate (ATP) release. Deoxyhemoglobin (deoxyHb), but not oxyhemoglobin, binds avidly and reversibly to band 3, the major erythrocyte membrane protein. Because band 3 associates with multiple metabolic, solute transport, signal transduction, and structural proteins, the hypothesis naturally arises that the O-dependent regulation of erythrocyte properties might be mediated by the reversible association of deoxyHb with band 3. To explore whether the band 3-deoxyHb interaction constitutes a "molecular switch" for regulating erythrocyte biology, we have generated transgenic mice with mutations in the deoxyHb-binding domain of band 3. One strain of mouse contains a "humanized" band 3 in which the N-terminal 45 residues of mouse band 3 are replaced by the homologous sequence from human band 3, including the normal human band 3 deoxyHb-binding site. The second mouse contains the same substitution as the first, except the deoxyHb site on band 3 (residues 12-23) has been deleted. Comparison of these animals with wild-type mice demonstrates that the following erythrocyte properties are controlled by the O-dependent association of hemoglobin with band 3: (1) assembly of a glycolytic enzyme complex on the erythrocyte membrane which is associated with a shift in glucose metabolism between the pentose phosphate pathway and glycolysis, (2) interaction of ankyrin with band 3 and the concomitant regulation of erythrocyte membrane stability, and (3) release of ATP from the red cell which has been linked to vasodilation.

Edited by Mike ShipstonMany erythrocyte processes and pathways, including glycolysis, the pentose phosphate pathway (PPP), KCl cotransport, ATP release, Na ؉ /K ؉ -ATPase activity, ankyrin-band 3 interactions, and nitric oxide (NO) release, are regulated by changes in O 2 pressure that occur as a red blood cell (RBC) transits between the lungs and tissues. The O 2 dependence of glycolysis, PPP, and ankyrin-band 3 interactions (affecting RBC rheology) are controlled by O 2 -dependent competition between deoxyhemoglobin (deoxyHb), but not oxyhemoglobin (oxyHb), and other proteins for band 3. We undertook the present study to determine whether the O 2 dependence of Na ؉ /K ؉ /2Cl ؊ cotransport (catalyzed by Na ؉ /K ؉ /2Cl ؊ cotransporter 1 [NKCC1]) might similarly originate from competition between deoxyHb and a protein involved in NKCC1 regulation for a common binding site on band 3. Using three transgenic mouse strains having mutated deoxyhemoglobin-binding sites on band 3, we found that docking of deoxyhemoglobin at the N terminus of band 3 displaces the protein with no lysine kinase 1 (WNK1) from its overlapping binding site on band 3. This displacement enabled WNK1 to phosphorylate oxidative stress-responsive kinase 1 (OSR1), which, in turn, phosphorylated and activated NKCC1. Under normal solution conditions, the NKCC1 activation increased RBC volume and thereby induced changes in RBC rheology. Because the deoxyhemoglobin-mediated WNK1 displacement from band 3 in this O 2 regulation pathway may also occur in the regulation of other O 2 -regulated ion transporters, we hypothesize that the NKCC1-mediated regulatory mechanism may represent a general pattern of O 2 modulation of ion transporters in erythrocytes.

Optimum care of female transplant recipients requires gynecologic care at several stages through the allogeneic hematopoietic stem cell transplantation (HCT) process. Sex-based considerations in women post-HCT span gynecologic sequelae of transplant along with assessment and maintenance of optimal sexual and gynecologic health. Pre-HCT, managing menstruation and abnormal uterine or genital bleeding, considering fertility preservation, and assessing for sexually transmitted infections, including human papillomavirus (HPV)-related disease and cervical cancer, enhance women's health. While inpatient during transplant when women are thrombocytopenic, menstrual bleeding requires suppression. Whenever graft-versus-host disease (GVHD) is assessed, screening for genital GVHD merits consideration. After the first 100 days, periodic assessments include obtaining a menstrual history, assessing ovarian function, and reviewing current hormonal use and contraindications to hormonal methods. Regular assessment for primary ovarian insufficiency, dyspareunia, and intimacy guides provision of contraception and hormone replacement options. As part of ongoing screening for genital GVHD and HPV-related disease, including sexually transmitted infections, periodic pelvic examinations are performed. Once successful long-term survival is achieved, planning for fertility may be considered. This article offers a comprehensive approach to these aspects of gynecologic care of patients throughout the trajectory of HCT and beyond into survivorship. We review the effects of HCT treatment on sexual health, ovarian function, and resulting menstrual changes and fertility challenges. Identification, treatment, and prevention of subsequent malignancies, including breast cancer, are discussed, with a focus on regular assessment of genital HPV disease and GVHD in long-term follow-up.