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Combinations of anti-cancer drugs can overcome resistance and provide new treatments 1 , 2 . The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or KRAS -mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or KRAS – TP53 double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments. A survey of potency and efficacy of 2,025 clinically relevant two-drug combinations against 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines identifies rare synergistic effects of anticancer drugs, informing rational combination treatments for specific cancer subtypes.

To evaluate longitudinal visual acuity (VA) outcomes in patients with endophthalmitis of any etiology at a university-affiliated hospital, using a modified Endophthalmitis Vitrectomy Study (EVS) framework comparing immediate pars plana vitrectomy (PPV), tap and injection (TAP), and TAP followed by PPV. The study included 125 patients diagnosed with endophthalmitis between 2011 and 2023. Patients were categorized into three treatment groups: TAP, PPV, and TAP followed by PPV. Data included demographics, etiology, causative organisms, adjunctive treatments, and VA at presentation, postoperative month 3 (POM3), and final follow-up. Statistical tests included -tests, ANOVA, Kaplan-Meier analysis, and Mann-Whitney -tests (p < 0.05). Mean patient age was 61 years; 67.2% were male, and 45.6% were transferred from another facility. Endogenous endophthalmitis was the most common etiology (32.8%), and bacterial organisms accounted for 41.6% of cases. Mean LogMAR VA at presentation was 1.984; 76.8% had VA ≤ 20/800. Fungal cases had better initial VA than bacterial (p < 0.001), though final VA was similar. Poorer initial VA was associated with primary PPV (p < 0.001). Final VA did not differ significantly among treatment groups, though patients with light perception (LP) or worse trended toward better outcomes with PPV. Systemic antimicrobials and dexamethasone injections were not associated with improved outcomes. Initial VA strongly influenced treatment. While overall outcomes were similar across groups, patients with LP or worse may benefit from primary PPV. EVS principles may apply broadly across endophthalmitis etiologies.

Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue, causing 405,000 deaths and 228 million cases in 2018. Understanding key metabolic processes in malaria parasites is critical to the development of new drugs to combat this major infectious disease. The Plasmodium glycolytic pathway is essential to the malaria parasite, providing energy for growth and replication and supplying important biomolecules for other essential Plasmodium anabolic pathways. Despite this overreliance on glycolysis, no current drugs target glycolysis, and there is a paucity of information on critical glycolysis targets. Our work addresses this unmet need, providing new mechanistic insights into this key pathway. Plasmodium parasites rely heavily on glycolysis for ATP production and for precursors for essential anabolic pathways, such as the methylerythritol phosphate (MEP) pathway. Here, we show that mutations in the Plasmodium falciparum glycolytic enzyme, phosphofructokinase ( Pf PFK9), are associated with in vitro resistance to a primary sulfonamide glycoside (PS-3). Flux through the upper glycolysis pathway was significantly reduced in PS-3-resistant parasites, which was associated with reduced ATP levels but increased flux into the pentose phosphate pathway. PS-3 may directly or indirectly target enzymes in these pathways, as PS-3-treated parasites had elevated levels of glycolytic and tricarboxylic acid (TCA) cycle intermediates. PS-3 resistance also led to reduced MEP pathway intermediates, and PS-3-resistant parasites were hypersensitive to the MEP pathway inhibitor, fosmidomycin. Overall, this study suggests that PS-3 disrupts core pathways in central carbon metabolism, which is compensated for by mutations in Pf PFK9, highlighting a novel metabolic drug resistance mechanism in P. falciparum . IMPORTANCE Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue, causing 405,000 deaths and 228 million cases in 2018. Understanding key metabolic processes in malaria parasites is critical to the development of new drugs to combat this major infectious disease. The Plasmodium glycolytic pathway is essential to the malaria parasite, providing energy for growth and replication and supplying important biomolecules for other essential Plasmodium anabolic pathways. Despite this overreliance on glycolysis, no current drugs target glycolysis, and there is a paucity of information on critical glycolysis targets. Our work addresses this unmet need, providing new mechanistic insights into this key pathway.

Regulatory T cell (Treg) adoptive cell therapy (ACT) represents an emerging strategy for restoring immune tolerance in autoimmune diseases. Tregs are commonly purified using a CD4 + CD25 + CD127 lo/- gating strategy, which yields a mixed population: 1) cells expressing the transcription factors, FOXP3 and Helios, that canonically define lineage stable thymic Tregs and 2) unstable FOXP3 + Helios - Tregs. Our prior work identified the autoimmune disease risk-associated locus and costimulatory molecule, CD226, as being highly expressed not only on effector T cells but also, interferon-γ (IFN-γ) producing peripheral Tregs (pTreg). Thus, we sought to determine whether isolating Tregs with a CD4 + CD25 + CD226 - strategy yields a population with increased purity and suppressive capacity relative to CD4 + CD25 + CD127 lo/- cells. After 14d of culture, expanded CD4 + CD25 + CD226 - cells displayed a decreased proportion of pTregs relative to CD4 + CD25 + CD127 lo/- cells, as measured by FOXP3 + Helios - expression and the epigenetic signature at the FOXP3 Treg-specific demethylated region (TSDR). Furthermore, CD226 - Tregs exhibited decreased production of the effector cytokines, IFN-γ, TNF, and IL-17A, along with increased expression of the immunoregulatory cytokine, TGF-β1. Lastly, CD226 - Tregs demonstrated increased in vitro suppressive capacity as compared to their CD127 lo/- counterparts. These data suggest that the exclusion of CD226-expressing cells during Treg sorting yields a population with increased purity, lineage stability, and suppressive capabilities, which may benefit Treg ACT for the treatment of autoimmune diseases.

Purpose The American Society of Clinical Oncology Clinical Practice guidelines recommend that non-physicians such as nurses, social workers, and psychologists should be prepared to discuss fertility and sexual concerns with patients. However, literature showed that the utilization rate of sexual and reproductive care for women with cancer remained low. We conducted a scoping review to describe non-physicians’ roles, barriers, and facilitators providing sexual and reproductive health (SRH) care to women of reproductive age with cancer. Methods We searched six databases for articles that met the following criteria: (1) English language; (2) original research; (3) non-physician providers; (4) women with cancer under age 50. We categorized barriers and facilitators at the system-, individual-, and clinical encounter-levels from providers’ and patients’ perspectives. Results We included 27 studies from 3451 retrieved articles. The majority of studies have a focus on fertility preservation or sexuality ( n  = 25). At the system level, the main barriers for non-physicians were lack of SRH care guidelines and collaborating experts. Concerns for patients included socioeconomic and geographic constraints in obtaining care. At the encounter level, providers and patients lacked experience discussing SRH. At the individual level, providers’ lack of knowledge in SRH treatment options and interprofessional collaboration and patients’ lack of awareness about treatment effects hindered SRH discussions. Facilitators include the availability of SRH programs and specialists, and rapport between providers and patients. Conclusions Supporting non-physicians to provide SRH services to women with cancer requires investment in clinical guidelines, interprofessional collaboration, and training in patient communication.

Objective: The Hyde Amendment and related policies limit or prohibit Medicaid coverage of abortion services in the United States. Most research on cost-related abortion barriers relies on clinic-based samples, but people who desire abortions may never make it to a healthcare center. To examine a novel, pre-abortion population, we analyzed a unique qualitative dataset of posts from Reddit, a widely used social media platform increasingly leveraged by researchers, to assess financial obstacles among anonymous posters considering abortion. Methods: In February 2020, we used Python to web-scrape the 250 most recent posts that mentioned abortion, removing all identifying information and usernames. After transferring all posts into NVivo, a qualitative software package, the team identified all datapoints related to cost. Three qualitatively trained evaluators established and applied codes, reaching saturation after 194 posts. The research team used a descriptive qualitative approach, using both inductive and deductive elements, to identify and analyze themes related to financial barriers. Results: We documented multiple cost-related deterrents, including lack of funds for both the procedure and attendant travel costs, inability to afford desired abortion modality (i.e., medication or surgical), and for some, consideration of self-managed abortion options due to cost barriers. Conclusions: Findings from this study underscore the centrality of cost barriers and third-party payer restrictions to stymying reproductive health access in the United States. Results may contribute to the growing evidence base and building political momentum focused on repealing the Hyde Amendment.

Compared with their heterosexual peers, sexual minority women (SMW; e.g., queer, bisexual, lesbian, pansexual) have an elevated risk for unintended pregnancy. A team of social science and clinical researchers qualitatively documented the multilevel pathways leading to this disparity, particularly the contexts of contraceptive use. From August 2017 to April 2018, we conducted focus groups and interviews with young adult cisgender SMW in 3 cities: Chicago, Illinois; Madison, Wisconsin; and Salt Lake City, Utah. Most participants reported experience with both penile–vaginal intercourse and contraception. However, they faced several queer-specific barriers to preventing unwanted pregnancy, including a comparative lack of self-concept as contraceptive users, fear of stigma from both queer and health care communities, use of less-effective methods because of infrequent penile–vaginal intercourse and a sense that longer-acting methods were “overkill,” and previous experiences of discrimination such as homophobia and gender-based violence. However, participants also reported ways that contraception could align with queer identity, including both taking advantage of noncontraceptive benefits and framing contraception as sex- and queer-positive. These facilitators can inform future efforts to help SMW better meet their pregnancy prevention needs.

Queer women and gender-expansive individuals assigned female at birth face barriers to achieving their reproductive health and family formation goals. Paradoxically, current literature in this area suggests that while queer individuals face higher rates of unwanted, unintended, or mistimed pregnancies, there are also significant barriers to achieving wanted pregnancies. Informed by principals of reproductive justice, this dissertation study aims to understand collective barriers to family formation, viewing both barriers to wanted pregnancies and barriers to avoiding pregnancy as stemming from similar root causes. This dissertation uses a modified grounded theory approach to examine how queer women and gender-expansive individuals relate and respond to pregnancy, including the role of sexual identity in shaping their experiences. This dissertation is comprised of three papers. The first paper outlines how queer women and gender-expansive individuals consider pregnancy and family planning in the context of their lives and identities and outlines the most salient factors in informing pregnancy desires. The second paper discusses the experiences of queer women and gender-expansive individuals seeking abortion, and the unique ways that queer identity shaped abortion experiences and attitudes. The third paper documents experiences in the healthcare system and the strategies that individuals use to meet their health needs despite barriers to queer-inclusive care. Collectively, these papers discuss the range of pregnancy experiences, the context in which queer individuals are making family formation and pregnancy decisions, as well as the significant influences on pregnancy desires and experiences for queer individuals. Findings from this dissertation have several implications for family planning and social work research and practice, as well as policy implications. Supporting queer individuals in a range of reproductive health and parenting options is vital to full recognition of queer individuals' bodily autonomy, affirming reproductive justice, and supporting participation in a fundamental human experience—family building.

Regulatory T cell (Treg) adoptive cell therapy (ACT) represents an emerging strategy for restoring immune tolerance in autoimmune diseases. Tregs are commonly purified using a CD4 CD25 CD127 gating strategy, which yields a mixed population: 1) cells expressing the transcription factors, FOXP3 and Helios, that canonically define lineage stable thymic Tregs and 2) unstable FOXP3 Helios Tregs. Our prior work identified the autoimmune disease risk-associated locus and costimulatory molecule, CD226, as being highly expressed not only on effector T cells but also, interferon-γ (IFN-γ) producing peripheral Tregs (pTreg). Thus, we sought to determine whether isolating Tregs with a CD4 CD25 CD226 strategy yields a population with increased purity and suppressive capacity relative to CD4 CD25 CD127 cells. After 14d of culture, expanded CD4 CD25 CD226 cells displayed a decreased proportion of pTregs relative to CD4 CD25 CD127 cells, as measured by FOXP3 Helios expression and the epigenetic signature at the Treg-specific demethylated region (TSDR). Furthermore, CD226 Tregs exhibited decreased production of the effector cytokines, IFN-γ, TNF, and IL-17A, along with increased expression of the immunoregulatory cytokine, TGF-β1. Lastly, CD226 Tregs demonstrated increased suppressive capacity as compared to their CD127 counterparts. These data suggest that the exclusion of CD226-expressing cells during Treg sorting yields a population with increased purity, lineage stability, and suppressive capabilities, which may benefit Treg ACT for the treatment of autoimmune diseases.

To identify the factors that have influenced dental hygienists to pursue post-graduate education opportunities, specifically dental (DDS, DMD) as compared to academic doctoral degrees, such as doctor of philosophy (PhD) or doctor of education (EdD). A convenience sample of dental hygienists with doctoral degrees were identified from multiple sources (n=140) and sent a 27-item web-based survey. Univariate logistic regression analysis was used to explore the influence of independent variables (respondents' demographic and personal characteristics, influential persons and experiences, encouraging and motivating factors) on the respondents' decision to pursue either a dental or an academic doctoral degree. Of the 140 potential participants, 69 (n=69) responded (49% response rate): 17 dental degree respondents, 46 academic degree respondents. In contrast to academic degree respondents, those with dental degrees graduated from dental hygiene programs more recently (p=0.03), spent less time working as a dental hygienist (p=0.01), considered themselves mechanically inclined (p=0.03), and preferred to learn a new skill rather than read about a current research study (p=0.002). Both groups agreed that working one-on-one with people was important to career satisfaction. Dental degree respondents were more likely to have been influenced or encouraged to pursue dentistry by dentists (p=0.01) and family (p=0.004). Academic degree respondents were more likely to have had experiences with a researcher/scientist (p=0.004) or had been influenced by an educator (p=0.01). Only 40% of all respondents reported that dental hygiene instructors were instrumental in encouraging their advanced education. Dental hygienists possessing characteristics similar to the academic degree respondents in this study should be encouraged to pursue academic doctoral education, providing the necessary skills to advance the dental hygiene profession.