Couple-Years of Protection Indicator: New Global Guidance for Updating Existing Methods and Adding New Methods.

BACKGROUND: Couple-years of protection (CYP) is an indicator that allows for monitoring and evaluating of family planning (FP) program performance through simple calculations. The CYP for each contraceptive method is calculated by multiplying the number of contraceptive commodity units distributed to clients over a 1-year period by a conversion factor that quantifies the duration of contraceptive protection provided per unit distributed. CYP calculations across methods were previously updated in 2000 and 2011, resulting in changes in methodology, factor inclusion, and specific methods. Since the 2011 update, changes and additions to the modern contraceptive method mix required new CYP conversion factors for 4 methods of contraception: Levoplant implant, progestin-only pills (POPs), Caya diaphragm, and the hormonal intrauterine device. METHODS: We conducted literature reviews of both published and gray literature and consulted with experts to identify updated data on continuation rates, duration of efficacy, and method effectiveness for the 4 methods. New CYP conversion factors were calculated for the 4 methods either by using the same calculation used previously for the method considering new data or, for new methods, using calculations for similar methods. RESULTS: New CYP conversion factors were assigned to the 4 methods of contraception covered in this update: Levoplant, 2.5 CYP per implant inserted; POPs, 0.0833 CYP per pack (i.e., 12 cycles per CYP); Caya diaphragm, 1 CYP per device, and hormonal intrauterine device, 4.8 CYP per device inserted. CONCLUSIONS: CYP is an important indicator for FP programs. As new methods of contraception are developed and new evidence is generated for current methods, the indicator may need to be updated. A standard process for updating and documenting future CYP updates is recommended.

Dynamic interactions between the extracellular matrix and estrogen activity in progression of ER+ breast cancer.

Metastatic, antiestrogen resistant estrogen receptor α positive (ER+) breast cancer is the leading cause of breast cancer deaths in USA women. While studies have demonstrated the importance of the stromal tumor microenvironment in cancer progression and therapeutic responses, effects on the responses of ER+ cancers to estrogen and antiestrogens are poorly understood, particularly in the complex in vivo environment. In this study, we used an estrogen responsive syngeneic mouse model to interrogate how a COL1A1-enriched fibrotic ECM modulates integrated hormonal responses in cancer progression. We orthotopically transplanted the ER+ TC11 cell line into wild-type (WT) or collagen-dense (Col1a1tm1Jae/+, mCol1a1) syngeneic FVB/N female mice. Once tumors were established, recipients were supplemented with 17ß-estradiol (E2), tamoxifen, or left untreated. Although the dense/stiff environment in mCol1a1 recipients did not alter the rate of E2-induced proliferation of the primary tumor, it fostered the agonist activity of tamoxifen to increase proliferation and AP-1 activity. Manipulation of estrogen activity did not alter the incidence of lung lesions in either WT or mCol1a1 hosts. However, the mCol1a1 environment enabled tamoxifen-stimulated growth of pulmonary metastases and further fueled estrogen-driven growth. Moreover, E2 remodeled peritumoral ECM architecture in WT animals, modifying alignment of collagen fibers and altering synthesis of ECM components associated with increased alignment and stiffness, and increasing FN1 and POSTN expression in the pulmonary metastatic niche. These studies demonstrate dynamic interactions between ECM properties and estrogen activity in progression of ER+ breast cancer, and support the need for therapeutics that target both ER and the tumor microenvironment.

17ß-Estradiol and ICI182,780 Differentially Regulate STAT5 Isoforms in Female Mammary Epithelium, With Distinct Outcomes.

Prolactin (PRL) and estrogen cooperate in lobuloalveolar development of the mammary gland and jointly regulate gene expression in breast cancer cells in vitro. Canonical PRL signaling activates STAT5A/B, homologous proteins that have different target genes and functions. Although STAT5A/B are important for physiological mammary function and tumor pathophysiology, little is known about regulation of their expression, particularly of STAT5B, and the consequences for hormone action. In this study, we examined the effect of two estrogenic ligands, 17ß-estradiol (E2) and the clinical antiestrogen, ICI182,780 (ICI, fulvestrant) on expression of STAT5 isoforms and resulting crosstalk with PRL in normal and tumor murine mammary epithelial cell lines. In all cell lines, E2 and ICI significantly increased protein and corresponding nascent and mature transcripts for STAT5A and STAT5B, respectively. Transcriptional regulation of STAT5A and STAT5B by E2 and ICI, respectively, is associated with recruitment of estrogen receptor alpha and increased H3K27Ac at a common intronic enhancer 10 kb downstream of the Stat5a transcription start site. Further, E2 and ICI induced different transcripts associated with differentiation and tumor behavior. In tumor cells, E2 also significantly increased proliferation, invasion, and stem cell-like activity, whereas ICI had no effect. To evaluate the role of STAT5B in these responses, we reduced STAT5B expression using short hairpin (sh) RNA. shSTAT5B blocked ICI-induced transcripts associated with metastasis and the epithelial mesenchymal transition in both cell types. shSTAT5B also blocked E2-induced invasion of tumor epithelium without altering E2-induced transcripts. Together, these studies indicate that STAT5B mediates a subset of protumorigenic responses to both E2 and ICI, underscoring the need to understand regulation of its expression and suggesting exploration as a possible therapeutic target in breast cancer.

Seroprevalence of pertussis in the Gambia: evidence for continued circulation of bordetella pertussis despite high vaccination rates.

BACKGROUND: Bordetella pertussis can cause severe respiratory disease and death in children. In recent years, large outbreaks have occurred in high-income countries; however, little is known about pertussis incidence in sub-Saharan Africa. METHODS: We evaluated antibody responses to pertussis toxin (Ptx) from individuals aged between 2 and 90 years in rural Gambia. IgG-Ptx was measured using luminex xMAP technology. IgG-Ptx geometric mean concentrations (GMC) and their 95% confidence intervals were calculated. The proportion seropositive (>20 EU/mL or ≥62.5 EU/mL) and GMCs were compared by age, sex, ethnic group, vaccination status, birth order and number of siblings per household using logistic and linear regression. RESULTS: 76.3% had anti-Ptx levels <20 EU/mL, 17.5% had concentrations between 20 and 62.5 EU/mL, 4.4% had concentrations between 62.5 and 125 EU/mL and 1.8% had concentrations ≥125 EU/mL. The overall Ptx antibody GMC was 6.4 EU/mL (95% confidence interval: 5.8-6.9). Higher antibody concentrations were observed in older populations with evidence for an increase in infection risk with increasing age (1.9% yearly increase, 95% confidence interval: 1.3-2.5). No child under 6 years of age had GMC above 62.5 EU/mL but 29.5% had concentrations between 20 and 62.5 EU/mL. CONCLUSIONS: These data provide evidence that B. pertussis is being transmitted within this population despite high vaccination coverage. Re-infection may occur implying that immunity from childhood vaccination may not be lifelong. In the absence of data on actual clinical cases of pertussis, seroprevalence studies remain valuable tools to assess the transmission dynamics of B. pertussis.

Prolactin activates ERα in the absence of ligand in female mammary development and carcinogenesis in vivo.

Resistance of estrogen receptor positive (ERα+) breast cancers to antiestrogens is a major factor in the mortality of this disease. Although activation of ERα in the absence of ligand is hypothesized to contribute to this resistance, the potency of this mechanism in vivo is not clear. Epidemiologic studies have strongly linked prolactin (PRL) to both development of ERα+ breast cancer and resistance to endocrine therapies. Here we employed genetically modified mouse models to examine the ability of PRL and cross talk with TGFα to activate ERα, using a mutated ERα, ERα(G525L), which is refractory to endogenous estrogens. We demonstrate that PRL promotes pubertal ERα-dependent mammary ductal elongation and gene expression in the absence of estrogen, which are abrogated by the antiestrogen, ICI 182,780 (ICI). PRL and TGFα together reduce sensitivity to estrogen, and 30% of their combined stimulation of ductal proliferation is inhibited by ICI, implicating ligand-independent activation of ERα as a component of their interaction. However, PRL/TGFα-induced heterogeneous ERα+ tumors developed more rapidly in the presence of ICI and contained altered transcripts for surface markers associated with epithelial subpopulations and increased signal transducer and activator of transcription 5b expression. Together, these data support strong interactions between PRL and estrogen on multiple levels. Ligand-independent activation of ERα suggests that PRL may contribute to resistance to antiestrogen therapies. However, these studies also underscore ERα-mediated moderation of tumor phenotype. In light of the high expression of PRL receptors in ERα+ cancers, understanding the actions of PRL and cross talk with other oncogenic factors and ERα itself has important implications for therapeutic strategies.