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The Metastatic Breast Cancer Project (MBCproject) is an ongoing research study that directly engages patients (pts) through social media and advocacy groups, and empowers them to share their samples, clinical information, and experiences. The goal is to create a publicly available dataset of linked genomic, clinical, and pt-reported data to enable research. In collaboration with pts, advocates, and advocacy groups, a website (MBCproject.org) was developed that allows pts with metastatic breast cancer (MBC) anywhere in the US or Canada to register. From 10/20/15-6/1/21, 6100 patients with MBC registered for the MBCproject. Registered pts are sent an online consent form that asks for permission to obtain and analyze their medical records and samples. Consented pts are sent a saliva and/or blood kit and asked to mail back a saliva sample, which is used to extract germline DNA, and/or a blood sample, which is used to extract germline DNA and cell free DNA (cfDNA). We contact participants’ medical providers to obtain medical records and a portion of their stored tumor biopsies. 3456 pts receiving care at over 1700 different institutions have consented to share medical records and tumor/saliva/blood samples and to have genomic analysis performed. Whole exome sequencing (WES) is performed on tumor DNA, germline DNA, and cfDNA; transcriptome sequencing (RNA-seq) is performed on tumor RNA. Medical records and pt-reported data are abstracted to create a detailed clinical record for each pt. Table 1 highlights clinical data collection, biospecimen acquisition, and genomic data generation to date. Examples of clinicogenomic analyses are shown in Table 2. De-identified linked genomic, clinical, and pt-reported data is shared regularly via public databases (mbcproject.org, cBioPortal, dbGaP, NCI Genomic Data Commons). To date, this data has been cited in over 40 publications. Study updates are shared with participants regularly. The MBCproject continues to enroll new patients, generate additional data, and perform integrated clinical and genomic analyses with the goal of building a dataset that is representative of patients with MBC. We have partnered with over 30 non-profit breast cancer advocacy groups. We also have several community engagement efforts underway to more directly reach patients in underrepresented communities, including partnerships with faith-based organizations and colleges/universities, as well as targeted engagement with the African American community. In addition, in partnership with Latinx patients, advocates, and researchers, a Spanish-language version of the MBCproject was launched in June 2021. Partnering directly with pts rapidly enables thousands of pts to remotely share tumors, blood, saliva, and medical records to accelerate research. The resulting publicly shared clinically annotated dataset is a resource that allows researchers to identify patients with specific phenotypes, who have often been challenging to identify with traditional approaches. Clinical data collection, biospecimen acquisition, and genomic data generation:NumberConsent signed (US & CA)3456 ptsPatient-reported data collected (demographics, diagnosis details, receptor status, clinical experiences, pathology details, sites of metastasis, treatments with start and stop dates3456 ptsMedical record received from clinical institution1365 ptsSaliva sample received from pt2124 ptsBlood sample received from pt1114 ptsTumor samples received from clinical institution631 tumor samples from 398 ptsWES from germline complete505 germline samplesWES from tumor (primary and metastatic) samples complete429 tumor samplesRNA-seq from tumor (primary and metastatic) samples complete351 tumor samplesULP-WGS from cfDNA (taken in metastatic setting) complete953 blood samplesWES from circulating tumor DNA (taken in metastatic setting) complete144 blood samples CohortConsented (US & CA)Tumor WES completeTumor RNA-seq completePts diagnosed < 40 yrs of age114615292De novo MBC1207158109Late recurrence (>5 years after dx)9099141Long term survivors (MBC > 10yrs)163138Resistance to CDK4/6 inhibitors70914839NED at time of f/u survey4305445Triple Negative Breast Cancer3304632Patients with 2 or more tumor biopsies/cfDNA samples collected by the MBCproject29810882 Citation Format: Nikhil Wagle, Corrie Painter, Elana Anastasio, Mary McGillicuddy, Esha Jain, Tania G. Hernandez, Brett N. Tomson, Beena Thomas, Daniel Abravanel, Dewey Kim, Sara Balch, Alyssa L. Damon, Shahrayz Shah, Rafael Ramos, Delia Sosa, Ilan Small, Colleen Nguyen, Sarah Winnicki, Taylor Cusher, Parker Chastain, Michael Dunphy, Jorge Gomez Tejeda Zanudo, Netsanet Tsegai, Lauren Sterlin, Ulcha F. Ulysse, Imani Boykin, Oyin Alao, Todd R. Golub. The metastatic breast cancer project: Generating the clinical and genomic landscape of metastatic breast cancer through patient-partnered research [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-19-01.

Objective To report on the effectiveness of a standardised core Maternity Waiting Home (MWH) model to increase facility deliveries among women living >10 km from a health facility. Design Quasi‐experimental design with partial randomisation at the cluster level. Setting Seven rural districts in Zambia. Population Women delivering at 40 health facilities between June 2016 and August 2018. Methods Twenty intervention and 20 comparison sites were used to test whether MWHs increased facility delivery for women living in rural Zambia. Difference‐in‐differences (DID) methodology was used to examine the effectiveness of the core MWH model on our identified outcomes. Main outcome measures Differences in the change from baseline to study period in the percentage of women living >10 km from a health facility who: (1) delivered at the health facility, (2) attended a postnatal care (PNC) visit and (3) were referred to a higher‐level health facility between intervention and comparison group. Results We detected a significant difference in the percentage of deliveries at intervention facilities with the core MWH model for all women living >10 km away (DID 4.2%, 95% CI 0.6–7.6, P = 0.03), adolescent women (10 km away (DID 18.1%, 95% CI 6.3–29.8, P = 0.002) and primigravida women living >10 km away (DID 9.3%, 95% CI 2.4–16.4, P = 0.01) and for women attending the first PNC visit (DID 17.8%, 95% CI 7.7–28, P 10 km from a healthcare facility, including adolescent women and primigravidas and attendance at the first PNC visit. Tweetable abstract A core MWH model increased facility delivery for women living >10 km from a health facility including adolescents and primigravidas in Zambia., Tweetable abstract A core MWH model increased facility delivery for women living >10 km from a health facility including adolescents and primigravidas in Zambia.

Summary Background Building financial management capacity is increasingly important in low‐ and middle‐income countries to help communities take ownership of development activities. Yet, many community members lack financial knowledge and skills. Methods We designed and conducted financial management trainings for 83 members from 10 community groups in rural Zambia. We conducted pre‐training and post‐training tests and elicited participant feedback. We conducted 28 in‐depth interviews over 18 months and reviewed financial records to assess practical application of skills. Results The training significantly improved knowledge of financial concepts, especially among participants with secondary education. Participants appreciated exercises to contextualize financial concepts within daily life and liked opportunities to learn from peers in small groups. Language barriers were a particular challenge. After trainings, sites successfully adhered to the principles of financial management, discussing the benefits they experienced from practicing accountability, transparency, and accurate recordkeeping. Conclusion Financial management trainings need to be tailored to the background and education level of participants. Trainings should relate financial concepts to more tangible applications and provide time for active learning. On‐site mentorship should be considered for a considerable time. This training approach could be used in similar settings to improve community oversight of resources intended to strengthen developmental initiatives.

Objective: To report on the effectiveness of a standardized core Maternity Waiting Home (MWH) model to increase facility deliveries and access to reproductive health services among women living farthest from a health facility (>10km) using facility-based data. Design: Quasi-experimental design. Setting: Seven rural districts in Zambia. Population: Women delivering at 40 health facilities between June 2016 to August 2018. Methods: 20 intervention sites and 20 comparison sites were used to test if MWHs increased access to reproductive health services for women living in rural Zambia. The difference-in-differences (DID) methodology was used to examine the effectiveness of the core MWH model on our primary outcomes. Main Outcome Measures: Differences in the change from baseline to endline in the percentage of women who: 1) traveled greater than 10 km for delivery, (2) attended a postnatal visit at 6 days postpartum, and (3) were referred to a higher-level health facility between intervention and comparison group. Results: We detected a significant difference for the percentage of deliveries at intervention facilities with the core MWH model for all women living >10km away (p=0.03), adolescent women ( 10km away (p=0.002), and primigravida women living >10km away (p=0.01). There were no significant differences for women attending a postnatal care visit at 6 days postpartum (p=0.07) or for women referred to the next level of care (p=0.29). Conclusion: The core MWH model was successful in reaching women with historically low rates of facility delivery, those living >10km from a healthcare facility, including adolescent women and primigravidas.

The Metastatic Breast Cancer Project (MBCproject) is an ongoing research study that directly engages patients (pts) through social media and advocacy groups, and empowers them to share their samples, clinical information, and experiences. The goal is to create a publicly available dataset of linked genomic, clinical, and pt-reported data to enable research. In collaboration with pts, advocates, and advocacy groups, a website (MBCproject.org) was developed that allows pts with metastatic breast cancer (MBC) anywhere in the US or Canada to register. From 10/20/15-3/31/20, 5708 women and men with MBC registered for the MBCproject. Registered pts are sent an online consent form that asks for permission to obtain and analyze their medical records and samples. Consented pts are sent a saliva and/or blood kit and asked to mail back a saliva sample, which is used to extract germline DNA, and/or a blood sample, which is used to extract germline DNA and cell free DNA (cfDNA). We contact participants’ medical providers to obtain medical records and a portion of their stored tumor biopsies. 3245 pts receiving care at over 1700 different institutions have consented to share medical records and tumor/saliva/blood samples and to have genomic analysis performed. Whole exome sequencing (WES) is performed on tumor DNA, germline DNA, and cfDNA; transcriptome sequencing (RNA-seq) is performed on tumor RNA. Medical records and pt-reported data are abstracted to create a detailed clinical record for each pt. Table 1 highlights clinical data collection, biospecimen acquisition, and genomic data generation to date. Examples of clinicogenomic analyses are shown in Table 2. De-identified linked genomic, clinical, and pt-reported data is shared regularly via public and semi-public databases (mbcproject.org, cBioPortal, dbGaP, NCI Genomic Data Commons). To date, this data has been cited in over 20 published journal articles. Study updates are shared with participants regularly. The MBCproject continues to enroll new patients, generate additional data, and perform integrated clinical and genomic analyses with the goal of building a dataset that is representative of patients with MBC. We have partnered with over 30 non-profit breast cancer advocacy groups. We also have several community engagement efforts underway to more directly reach patients in underrepresented communities, including partnerships with faith-based organizations and colleges/universities, as well as targeted engagement with the African American community. In addition, in partnership with Latinx patients, advocates, and researchers, the project has been translated into Spanish and is expected to launch in late 2020. Partnering directly with pts rapidly enables thousands of pts to remotely share tumors, blood, saliva, and medical records to accelerate research. The resulting publicly shared clinically annotated database is a resource that allows researchers to identify patients with specific phenotypes, who have often been challenging to identify with traditional approaches. Clinical data collection, biospecimen acquisition, and genomic data generation:NumberConsent signed (US & CA)3245 ptsSurvey #1 submitted(demographics, diagnosis details, receptor status, clinical experiences)3245 ptsSurvey #2 submitted(pathology details, sites of metastasis, treatments with start and stop dates)1638 ptsMedical record received1352 ptsSaliva sample received2004 ptsBlood sample received1121 ptsTumor samples received585 tumor samples from 424 ptsDigital image of tumor slide H&E generated585 tumor samplesWES from germline complete458 germline samplesWES from tumor (primary and metastatic) samples complete343 tumor samplesRNA-seq from tumor (primary and metastatic) samples complete228 tumor samplesULP-WGS from cfDNA (taken in metastatic setting) complete993 blood samplesWES from circulating tumor DNA (taken in metastatic setting) complete143 blood samples CohortConsented (US & CA)Tumor WES completeTumor RNA-seq completePts diagnosed < 40 yrs of age107312071De novo MBC112712183Late recurrence (>5 years after dx)8307752Long term survivors (MBC > 10yrs)158115Resistance to CDK4/6 inhibitors70914839NED at time of f/u survey4238939Triple Negative Breast Cancer3107531Patients with 2 or more tumor biopsies / cfDNA samples collected by the MBCproject2876138 Citation Format: Nikhil Wagle, Corrie Painter, Elana Anastasio, Michael Dunphy, Mary McGillicuddy, Esha Jain, Brett Tomson, Tania G. Hernandez, Beena Thomas, Dewey Kim, Alyssa L. Damon, Shahrayz Shah, Rafael Ramos, Colleen Nguyen, Lee O'Neil, Sarah Winnicki, Sara Balch, Rachel Stoddard, Taylor Cusher, Parker Chastain, Jorge Gomez Tejeda Zanudo, Jorge Buendia-Buendia, Ofir Cohen, Netsanet Tsegai, Lauren Sterlin, Ulcha F. Ulysse, Imani Boykin, Kate Sine, Oyin Alao, Jacqueline Lucia, Eric S. Lander, Todd R. Golub. The metastatic breast cancer project: Generating the clinical and genomic landscape of metastatic breast cancer through patient-partnered research [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-18-01.

Background The potency of T regulatory (TREG) cells to inhibit T helper (Th)-driven immune cell responses has been linked to increased intracellular cyclic-AMP (cAMP) levels of TREG cells. In an ovalbumin (OVA)-driven allergic asthma mouse model, moderate aerobic exercise increases TREG cell function in a contact-dependent manner that leads to a significant reduction in chronic inflammation and restoration of lung function. However, the mechanism, whereby exercise increases TREG function, remains unknown and was the focus of these investigations. Exercise can communicate with TREG cells by their expression of β2-adrenergic receptors (β2-AR). Activation of these receptors results in an increase in intracellular levels of cyclic-AMP, potentially creating a potent inhibitor of Th cell responses. Results For the allergic asthma model, female wildtype BALB/c mice were challenged with OVA, and exercised (13.5 m/min for 45 min) 3×/week for 4 weeks. TREG cells were isolated from all mouse asthma/exercise groups, including β2-AR−/− mice, to test suppressive function and intracellular cAMP levels. In these studies, cAMP levels were increased in TREG cells isolated from exercised mice. When β2-AR expression was absent on TREG cells, cAMP levels were significantly decreased. Correlatively, their suppressive function was compromised. Next, TREG cells from all mouse groups were tested for suppressive function after treatment with either a pharmaceutical β2-adrenergic agonist or an effector-specific cAMP analogue. These experiments showed TREG cell function was increased when treated with either a β2-adrenergic agonist or effector-specific cAMP analogue. Finally, female wildtype BALB/c mice were antibody-depleted of CD25+CD4+ TREG cells (anti-CD25). Twenty-four hours after TREG depletion, either β2-AR−/− or wildtype TREG cells were adoptively transferred. Recipient mice underwent the asthma/exercise protocols. β2-AR−/− TREG cells isolated from these mice showed no increase in TREG function in response to moderate aerobic exercise. Conclusion These studies offer a novel role for β2-AR in regulating cAMP intracellular levels that can modify suppressive function in TREG cells.

Studies have indicated increased incidence and severity of allergic asthma due to western lifestyle and increased sedentary activity. Investigations also indicate that exercise reduces the severity of asthma; however, a mechanism of action has not been elucidated. Additional work implicates re-distribution of T helper (Th) cells in mediating alterations of the immune system as a result of moderate aerobic exercise in vivo. We have previously reported that exercise decreases T helper 2 (Th2) responses within the lungs of an ovalbumin (OVA)-sensitized murine allergic asthma model. Therefore, we hypothesized that exercise alters the migration of OVA-specific Th cells in an OVA-challenged lung. To test this hypothesis, wildtype mice received OVA-specific Th cells expressing a luciferase-reporter construct and were OVA-sensitized and exercised. OVA-specific Th cell migration was decreased in OVA-challenged lungs of exercised mice when compared to their sedentary controls. Surface expression levels of lung-homing chemokine receptors, CCR4 and CCR8, on Th cells and their cognate lung-homing chemokine gradients revealed no difference between exercised and sedentary OVA-sensitized mice. However, transwell migration experiments demonstrated that lung-derived Th cells from exercised OVA-sensitized mice exhibited decreased migratory function versus controls. These data suggest that Th cells from exercised mice are less responsive to lung-homing chemokine. Together, these studies demonstrate that moderate aerobic exercise training can reduce the accumulation of antigen-specific Th cell migration into an asthmatic lung by decreasing chemokine receptor function.

We have shown moderate aerobic exercise can increase both the number and function of T regulatory (TREG) cells that suppress Th2 responses of an ovalbumin (OVA)-driven murine asthma model by an unknown mechanism. Exercise can communicate with TREG cells with the systemic release of catecholamines that bind to Beta-2-adrenergic receptors (β2-AR) and generate cAMP signals that can affect cell function. In these studies, we investigated a role for β2-AR in the exercise-mediated modulation of TREG cell function. For these studies, TREG cells (CD4+CD25+) were depleted from female BALB/cJ mice by i.v. injection of anti-CD25. Either 500,000 wt or β2-AR-/- TREG cells were adoptively transferred into the TREG-depleted BALB/cJ mice. Mice were sensitized/challenged with OVA to mimic allergic asthma pathogenesis. Mice were moderately exercised 45 min post-OVA challenge on a treadmill for 1hr 3x/wk for 4wks. Upon protocol completion, mice were examined for changes in TREG cell suppressive function and their resulting TREG cAMP levels. Our results show that exercise increases TREG function in vitro as compared with sedentary controls. However, the increase in TREG function of exercised TREG cells was abrogated in the absence of β2-ARs. We conclude that moderate aerobic exercise attenuates asthma-related airway inflammation via a mechanism that involves increased TREG cell function modulated by their expression of β2-ARs and subsequent production of cAMP.