Explore the vast range of titles available.

\"The U.S. political leaders of 2016 abandon the radioactive planet they've destroyed and harness the power of humanity's last hope: The Splitter, a colossal machine designed to manufacture a bright new reality for them to infiltrate and corrupt\"--Page 4 of cover.

Background While the introduction of HIV Pre-Exposure Prophylaxis (PrEP) as an HIV prevention strategy has allowed women to exercise more control over the reduction of HIV transmission rates, adolescent girls and young women in Sub-Saharan Africa continue to experience higher rates of HIV infections and bear the greatest disease burden. Understanding progress in PrEP uptake among adolescent girls and young women would enhance risk reduction in this vulnerable population. The Determined, Resilient, AIDS-Free, Mentored and Safe women (DREAMS) Initiative plays a key role in this risk reduction strategy. Methods We performed a qualitative study to explore facilitators and barriers to PrEP implementation and assess factors effecting initiation and persistence on PrEP among adolescent girls and young women enrolled in the DREAMS Initiative at Pamoja Community Based Organization in Kisumu, Kenya. We conducted key informant interviews ( n  = 15) with Pamoja Community Based Organization staff, health care providers and community leaders. Additionally, we conducted focus group discussions with young women receiving PrEP and peer mentors ( n  = 40). We performed a directed content analysis using the Consolidated Framework for Implementation Research to organize the identified facilitators and barriers. Results We found that the use of the safe space model, decentralization of PrEP support and delivery, peer mentors, effective linkage to local health care facilities, the sensitization of parents and male sexual partners, disclosure of PrEP use by beneficiaries, active stakeholder involvement and community engagement were among some of the facilitators to PrEP uptake. Barriers to PrEP implementation, initiation and persistence included stigma associated with the use of anti-retroviral drugs, drug side effects, frequent relocation of beneficiaries, limited resources for routine screening and medication monitoring, and a limited number of qualified health care workers for PrEP distribution and administration. Conclusion Overall, the community roll-out of PrEP within the DREAMS Initiative was successful due to a number of key facilitating factors, which ultimately led to successful PrEP implementation, increased PrEP initiation and enhanced persistence among adolescent girls and young women. The identified barriers should be addressed so that a larger scale-up of PrEP roll-out is possible in the future.

Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease. Targeting solid tumours by chimeric antigen receptor (CAR) T cells require strategies that improve trafficking and effector function of these cells in the immunologically hostile cancer microenvironment. Here, authors show that CAR T cells engineered with incorporation of the CD28 transmembrane domain to the 4-1BB costimulatory domain and a membrane-bound form of IL-12 can achieve efficient anti-tumour activity and promote systemic disease targeting via regional T cell delivery in multi-metastatic disease models.

Background Aging is the greatest risk factor for breast cancer, and although epithelial cells are the source of carcinomas, epithelial changes alone do not fully explain cancer susceptibility. Fibroblasts and macrophages are key stromal constituents around the cells of origin for cancer in breast tissue. With age, macrophages surrounding terminal ductal lobular units (TDLUs) become increasingly immunosuppressive. CD105 + fibroblasts intercalate within TDLUs, drive luminal differentiation, and give rise to immunosuppressive cancer-associated fibroblasts in other tissues. We propose that differences in fibroblasts are a crucial component of the stroma that shapes cancer susceptibility. Methods Primary peri-epithelial fibroblast cultures were established from prophylactic and reduction mammoplasties from 30 women ranging in age from 16 to 70 years and from  BRCA1 mutation carriers. Growth characteristics, transcriptional profiles, differentiation potential, and secreted proteins were profiled for fibroblast subtypes from diverse donors. Co-cultures with fibroblasts, macrophages, and T cells were used to ascertain the functional role played by CD105 + fibroblasts in immune cell modulation. Results We found that peri-epithelial CD105 + fibroblasts are enriched in older women as well as women who carry BRCA1 mutations. These CD105 + fibroblasts exhibit robust adipogenesis and secrete factors related to macrophage polarization. Macrophages cocultured with fibroblasts better maintain or enhance polarization states than media alone. CD105 + fibroblasts increased expression of immunosuppressive macrophage genes. CD105 + fibroblasts supported anti-inflammatory macrophage-mediated suppression of T cell proliferation, whereas CD105 − fibroblasts significantly reduced the suppressive effect of anti-inflammatory macrophages on T cell proliferation. Conclusions Establishment of a coculture system to dissect the molecular circuits between CD105 + fibroblasts and macrophages that drive immunosuppressive macrophage polarization has broad utility in understanding mammary gland development and events that precede cancer initiation. CD105 + fibroblasts and macrophages may coordinate to suppress immunosurveillance and increase breast cancer susceptibility.

BackgroundThe immune suppressive tumor microenvironment (TME) that inhibits T cell infiltration, survival, and antitumor activity has posed a major challenge for developing effective immunotherapies for solid tumors. Chimeric antigen receptor (CAR)-engineered T cell therapy has shown unprecedented clinical response in treating patients with hematological malignancies, and intense investigation is underway to achieve similar responses with solid tumors. Immunologically cold tumors, including prostate cancers, are often infiltrated with abundant tumor-associated macrophages (TAMs), and infiltration of CD163+ M2 macrophages correlates with tumor progression and poor responses to immunotherapy. However, the impact of TAMs on CAR T cell activity alone and in combination with TME immunomodulators is unclear.MethodsTo model this in vitro, we utilized a novel co-culture system with tumor cells, CAR T cells, and polarized M1 or M2 macrophages from CD14+ peripheral blood mononuclear cells collected from healthy human donors. Tumor cell killing, T cell activation and proliferation, and macrophage phenotypes were evaluated by flow cytometry, cytokine production, RNA sequencing, and functional blockade of signaling pathways using antibodies and small molecule inhibitors. We also evaluated the TME in humanized mice following CAR T cell therapy for validation of our in vitro findings.ResultsWe observed inhibition of CAR T cell activity with the presence of M2 macrophages, but not M1 macrophages, coinciding with a robust induction of programmed death ligand-1 (PD-L1) in M2 macrophages. We observed similar PD-L1 expression in TAMs following CAR T cell therapy in the TME of humanized mice. PD-L1, but not programmed cell death protein-1, blockade in combination with CAR T cell therapy altered phenotypes to more M1-like subsets and led to loss of CD163+ M2 macrophages via interferon-γ signaling, resulting in improved antitumor activity of CAR T cells.ConclusionThis study reveals an alternative mechanism by which the combination of CAR T cells and immune checkpoint blockade modulates the immune landscape of solid tumors to enhance therapeutic efficacy of CAR T cells.

SARS-CoV-2 infection during pregnancy was associated with maternal mortality and adverse birth outcomes in the pre-Omicron era, including a stillbirth rate of 5.6% in Botswana. We re-evaluated these outcomes in the Tsepamo Study during the Omicron era. We assessed maternal mortality and adverse birth outcomes for all singleton pregnancies from mid-November 2021 (the start of the Omicron era) to mid-August 2022 at nine Tsepamo sites, among individuals with documented SARS-CoV-2 screening PCR or antigen tests and known HIV status. Of 9,705 women routinely screened for SARS-CoV-2 infection at delivery (64% of deliveries at these sites), 373 (3.8%) tested positive. Women with HIV were as likely to test positive for SARS-CoV-2 (77/1833, 4.2%) as women without HIV (293/6981, 4.2%) (p = 1.0). There were 5 recorded maternal deaths (0.03%), one occurring in a woman with a positive SARS-CoV-2 test result. In contrast, maternal mortality was 3.7% and 0.1% in those with and without SARS-CoV-2, respectively, during the pre-Omicron era. In the Omicron era, there were no differences among infants exposed or unexposed to SARS-CoV-2 in overall adverse birth outcomes (28.1% vs 29.6%; aRR 1.0, 95%CI 0.8–1.1), severe adverse birth outcomes (11.9 vs 10.6%; aRR 1.1, 95%CI 0.8–1.5), preterm delivery (15.1% vs 14.9%; aRR 1.0, 95%CI 0.8–1.3), or stillbirth (1.9% vs 2.3%; aRR 0.8, 95%CI 0.4–1.7). Adverse outcomes among those exposed to both HIV and SARS-CoV-2 were similar to those exposed to HIV alone (31.2% vs. 33.1%; aRR 0.9, 95%CI 0.6–1.3; p = 0.5). Maternal mortality was far lower in Botswana during the Omicron era than in the pre-Omicron era, and adverse birth outcomes were no longer significantly impacted by exposure to SARS-CoV-2 either overall or with HIV co-exposure. Increased population immunity to SARS-CoV-2, less stress on the hospital systems in the Omicron era, and possible differences in viral pathogenicity may combine to explain these findings.

BackgroundThe immune suppressive tumor microenvironment (TME) that inhibits T cell infiltration, survival, and anti-tumor activity has posed a major challenge for developing effective immunotherapies for solid tumors. Chimeric antigen receptor T cell therapy has shown unprecedented clinical response in treating patients with hematological malignancies, and intense investigation is underway to achieve similar responses with solid tumors. Immunologically cold tumors, including prostate cancers, are often infiltrated with abundant macrophages, and infiltration of M2 macrophages correlates with metastasis and poor prognosis.MethodsTo model this in vitro, we utilized a novel co-culture system with tumor cells, prostate stem cell antigen (PSCA)-directed CAR T cells, and polarized macrophages. To investigate the TME in vivo, we took advantage of ”humanized” MISTRG mice, which are immunocompromised mice with knocked-in human genes that support human hematopoiesis and efficient tumor-infiltration of myeloid cell populations. Humanized MISTRG mice were intratibially engrafted with LAPC9 tumor cells to model bone metastatic disease.ResultsWe observed significant hampering of PSCA-CAR T cell activity in vitro with the presence of M2 macrophages, but not M1 macrophages, coinciding with a robust induction of PD-L1 in both tumor cells and macrophages. We also observed PD-L1 expression in tumor-associated macrophages infiltrating tumors following PSCA-CAR T cell therapy in the humanized mice. Anti-PD-L1 monoclonal antibodies in combination with CAR-T cell therapy altered phenotype and survival of M2 macrophages, resulting in improved anti-tumor activity of PSCA-CAR T cells in the presence of M2 macrophages.ConclusionsRecently, immune checkpoint (IC) blockade (ICB) has been utilized in combination with chimeric antigen receptor (CAR) T cell therapy, with the notion that induction of immune responses with CAR T cells may instigate checkpoint pathways in immunologically cold tumors that would otherwise not respond to ICB. This study gives insights to a mechanism by which CAR T cells and ICB work in synergy to modulate immune landscape of immunologically cold tumors, and our ongoing studies will continue to elucidate the TME-mediated immunosuppression of CAR T cell therapy.

Background Adolescent girls are three times more likely to be living with HIV than boys of the same age. Prior studies have found associations between adolescent pregnancies and increased maternal morbidity and infant mortality, but few studies have assessed the impact of HIV infection on maternal and infant outcomes in adolescents. Methods The Tsepamo Study abstracts maternal and infant data from obstetric records in government maternity wards in Botswana. We assessed maternal complications and adverse birth outcomes for all singleton pregnancies from August 2014 to August 2020 at eighteen Tsepamo sites among adolescents (defined as 10–19 years of age) and adults (defined as 20–35 years of age), by HIV status. Univariate and multivariate logistic regression using a complete case analysis method were used to evaluate differences in outcomes. Results This analysis included 142,258 singleton births, 21,133 (14.9%) to adolescents and 121,125 (85.1%) to adults. The proportion of adults living with HIV ( N  = 22,114, 22.5%) was higher than adolescents ( N  = 1593, 7.6%). The proportion of most adverse birth outcomes was higher in adolescents. Among adolescents, those with HIV had increased likelihoods of anemia (aOR = 1.89, 95%CI 1.66, 2.15) and cesarean sections (aOR = 1.49, 95%CI 1.3,1.72), and infants with preterm birth (aOR = 1.15, 95%CI 1.0, 1.32), very preterm birth (aOR = 1.35, 95%CI 1.0,1.8), small for gestational age (aOR = 1.37, 95%CI 1.20,1.58), and very small for gestational age (aOR = 1.46, 95%CI 1.20, 1.79). Conclusions Adolescent pregnancy and adolescent HIV infection remain high in Botswana. Adolescents have higher risk of adverse maternal and infant birth outcomes than adults, with the worst outcomes among adolescents living with HIV. Linking HIV prevention and family planning strategies for this age group may help minimize the number of infants with poor birth outcomes among this already vulnerable population .

The DREAMS (Determined, Resilient, Empowered, AIDS-free, Mentored, Safe) Initiative works to reduce HIV infection among adolescent girls and young women (AGYW) through prevention interventions including Pre-Exposure Prophylaxis (PrEP). Pamoja CBO in Kisumu, Kenya implemented DREAMS. We describe PrEP initiation and persistence in 549 AGYW who started PrEP through Pamoja and factors associated with discontinuation. Median persistence time was 308 days (95% CI 245, 382) with 59% of AGYW discontinuing by the end of the study. The most common reasons for stopping PrEP were lack of perceived risk (27.9%) and relocation (18.7%). In the multivariable model, only age < 18 was associated with stopping PrEP. Younger age was associated with shorter time to discontinuation. Implementing PrEP through DREAMS was successful in supporting initiation of PrEP for AGYW. However, low rates of persistence at 1 year emphasizes the need for strategies to support PrEP persistence if HIV elimination is to be achieved.