To Address Women's Health Inequity, It Must First Be Measured.

Research and data collection related to what is historically known as "women's health" is consistently underfunded and marginalizes the health risks and experiences of women of color and transgender people. In the wake of the pandemic, the United States has an opportunity to redesign and reimagine a modern public health data infrastructure that centers equity and elevates the health and well-being of under-represented communities, including the full spectrum of gender identities. This piece offers a blueprint for transformational change in how the United States collects, interprets, and shares critical data to deliver greater health justice for all.

The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice.

Fanconi anemia is a genetic bone marrow failure syndrome. The current treatment options are suboptimal and do not prevent the eventual onset of aplastic anemia requiring bone marrow transplantation. We previously showed that resveratrol, an antioxidant and an activator of the protein deacetylase Sirt1, enhanced hematopoiesis in Fancd2 mutant mice and improved the impaired stem cell quiescence observed in this disease. Given that Sirt1 is important for the function of hematopoietic stem cells, we hypothesized that Sirt1 activation may improve hematopoiesis. Indeed, Fancd2(-/-) mice and wild-type mice treated with the selective Sirt1 activator SRT3025 had increased numbers of hematopoietic stem and progenitor cells, platelets and white blood cells. SRT3025 was also protective against acetaldehyde-induced hematopoietic damage. Unlike resveratrol, however, SRT3025 did not affect stem cell quiescence, suggesting distinct mechanisms of action. Conditional deletion of Sirt1 in hematopoietic cells did not abrogate the beneficial effects of SRT3025, indicating that the drug did not act by directly stimulating Sirt1 in stem cells, but must be acting indirectly via extra-hematopoietic effects. RNA-Seq transcriptome analysis revealed the down-regulation of Egr1-p21 expression, providing a potential mechanism for improved hematopoiesis. Overall, our data indicate that SRT3025 or related compounds may be beneficial in Fanconi anemia and other bone marrow failure syndromes.

Oxymetholone therapy of fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling.

Androgens are widely used for treating Fanconi anemia (FA) and other human bone marrow failure syndromes, but their mode of action remains incompletely understood. Aged Fancd2(-/-) mice were used to assess the therapeutic efficacy of oxymetholone (OXM) and its mechanism of action. Eighteen-month-old Fancd2(-/-) mice recapitulated key human FA phenotypes, including reduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia. As in humans, chronic OXM treatment significantly improved these hematological parameters and stimulated the proliferation of hematopoietic stem and progenitor cells. RNA-Seq analysis implicated downregulation of osteopontin as an important potential mechanism for the drug's action. Consistent with the increased stem cell proliferation, competitive repopulation assays demonstrated that chronic OXM therapy eventually resulted in stem cell exhaustion. These results expand our knowledge of the regulation of hematopoietic stem cell proliferation and have direct clinical implications for the treatment of bone marrow failure.

Evaluation of resveratrol and N-acetylcysteine for cancer chemoprevention in a Fanconi anemia murine model.

Fanconi anemia (FA) patients suffer from progressive bone marrow failure and often develop cancers. Previous studies showed that antioxidants tempol and resveratrol (RV) delayed tumor onset and reduced hematologic defects in FA murine models, respectively. Here we tested whether antioxidants N-acetylcysteine (NAC) or RV could delay cancer in tumor prone Fancd2(-/-) /Trp53(+/-) mice. Unlike tempol, neither compound had any significant chemopreventive effect in this model. We conclude that not all anti-oxidants are chemopreventive in FA. In addition, when given to Fancd2(-/-) mice, NAC helped maintain Fancd2(-/-) KSL cells in quiescence while tempol did not. The mechanisms behind the different actions of these antioxidants await further investigation.

Fancd2 and p21 function independently in maintaining the size of hematopoietic stem and progenitor cell pool in mice.

Fanconi anemia patients suffer from progressive bone marrow failure. An overactive p53 response to DNA damage contributes to the progressive elimination of Fanconi anemia hematopoietic stem and progenitor cells (HSPC), and hence presents a potential target for therapeutic intervention. To investigate whether the cell cycle regulatory protein p21 is the primary mediator of the p53-dependent stem cell loss, p21/Fancd2 double-knockout mice were generated. Surprisingly double mutant mice displayed even more severe loss of HSPCs than Fancd2(-/-) single mutants. p21 deletion did not rescue the abnormal cell cycle profile and had no impact on the long-term repopulating potential of Fancd2(-/-) bone marrow cells. Collectively, our data indicate that p21 has an indispensable role in maintaining a normal HSPC pool and suggest that other p53-targeted factors, not p21, mediate the progressive elimination of HSPC in Fanconi anemia.

The value of advocacy in obstetrics and maternal-fetal medicine.

PURPOSE OF REVIEW: To show that advocacy on behalf of an individual or organization has improved the practice of obstetrics and maternal-fetal medicine. RECENT FINDINGS: Advocacy by an individual or a large group aims to influence public policy and resource allocation decisions within political, economic, and social systems and institutions. For obstetrician-gynecologists and maternal-fetal medicine physicians, there is a health policy medical practice intersection that may be often overlooked. In the areas of research, reimbursement, federal policies surrounding maternity care, and quality improvement, physician leaders have influenced the policymaking process and can improve upon it in the future. SUMMARY: Because of advocacy efforts by organizations whose members may include physicians and patients, pregnant women will have access to better quality of care, and physicians will be better off. Also, quality measures that will be implemented will make sense to those who must comply with them because of expert involvement. Advocacy is an investment for the future of the practice of obstetrics and maternal-fetal medicine - to ensure that the workforce is strengthened and that the care of women and their babies is the best it can be.

Ten Years of TAKE 10!(®): Integrating physical activity with academic concepts in elementary school classrooms.

OBJECTIVE: Current literature supports the link between physical activity (PA) or fitness and a child's ability to achieve academically; however, little structured activity time is incorporated into elementary school classrooms. This paper explores the impact of a classroom-based PA program, TAKE 10!, and health-academic integration through existing state and federal policy and programming. METHODS: Evidence from journal articles, published abstracts, and reports were examined to summarize the impact of TAKE 10! on student health and other outcomes. This paper reviews 10 years of TAKE 10! studies and makes recommendations for future research. RESULTS: Teachers are willing and able to implement classroom-based PA integrated with grade-specific lessons (4.2 days/wk). Children participating in the TAKE 10! program experience higher PA levels (13%>), reduced time-off-task (20.5%), and improved reading, math, spelling and composite scores (p<0.01). Furthermore, students achieved moderate energy expenditure levels (6.16 to 6.42 METs) and studies suggest that BMI may be positively impacted (decreases in BMI z score over 2 years [P<0.01]). CONCLUSION: TAKE 10! demonstrates that integrating movement with academics in elementary school classrooms is feasible, helps students focus on learning, and enables them to realize improved PA levels while also helping schools achieve wellness policies.

Molecular steps of G-overhang generation at human telomeres and its function in chromosome end protection.

Telomeric G-overhangs are required for the formation of the protective telomere structure and telomerase action. However, the mechanism controlling G-overhang generation at human telomeres is poorly understood. Here, we show that G-overhangs can undergo cell cycle-regulated changes independent of telomerase activity. G-overhangs at lagging telomeres are lengthened in S phase and then shortened in late S/G2 because of C-strand fill-in, whereas the sizes of G-overhangs at leading telomeres remain stable throughout S phase and are lengthened in G2/M. The final nucleotides at measurable C-strands are precisely defined throughout the cell cycle, indicating that C-strand resection is strictly regulated. We demonstrate that C-strand fill-in is mediated by DNA polymerase alpha (polalpha) and controlled by cyclin-dependent kinase 1 (CDK1). Inhibition of CDK1 leads to accumulation of lengthened G-overhangs and induces telomeric DNA damage response. Furthermore, depletion of hStn1 results in elongation of G-overhangs and an increase in telomeric DNA damage. Our results suggest that G-overhang generation at human telomeres is regulated by multiple tightly controlled processes and C-strand fill-in is under the control of polalpha and CDK1.

Identification of a novel phosphorylation site, Ser-170, as a regulator of bad pro-apoptotic activity.

Bad is a pro-apoptotic member of the Bcl-2 family of proteins that is thought to exert a death-promoting effect by heterodimerization with Bcl-X(L), nullifying its anti-apoptotic activity. Growth factors may promote cell survival at least partially through phosphorylation of Bad at one or more of Ser-112, -136, or -155. Our previous work showed that Bad is also phosphorylated in response to cytokines at another site, which we now identify as Ser-170. The functional role of this novel phosphorylation site was assessed by site-directed mutagenesis and analysis of the pro-apoptotic function of Bad in transiently transfected HEK293 and COS-7 cells or by stable expression in the cytokine-dependent cell line, MC/9. In general, mutation of Ser-170 to Ala results in a protein with increased ability to induce apoptosis, similar to the S112A mutant. Mutation of Ser-170 to Asp, mimicking a constitutively phosphorylated site, results in a protein that is virtually unable to induce apoptosis. Similarly, the S112A/S170D double mutant does not cause apoptosis in HEK293 and MC/9 cell lines. These data strongly suggest that phosphorylation of Bad at Ser-170 is a critical event in blocking the pro-apoptotic activity of Bad.