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Key Points Since the 1940s, inhibitors of thymidylate biosynthesis have remained among the most effective chemotherapies used in the treatment of cancer The enzyme thymidylate synthase (TS) is a key metabolic bottleneck in the synthesis of thymidine monophosphate required for DNA replication in tumour cells and, therefore, represents an important therapeutic target The molecular consequences of TS inhibition can be complex and vary depending on the type of inhibitor, the tumour type and the expression levels of enzymes involved in drug metabolism Inhibitors of TS fall into two major classes, the fluoropyrimidines and antifolates; these TS-targeted therapies remain the foundation of many combination chemotherapies used in patients with difficult-to-treat cancers The application of existing TS-targeted agents continues to expand, with new approvals of these drugs for the treatment of solid tumours New combination therapeutic strategies have emerged and are entering clinical trials, such as those targeting dUTPase to exploit the uracil-misincorporation pathway and defective DNA repair that occurs during TS inhibition Chemotherapeutic agents targeting thymidylate biosynthesis, and particularly the enzyme thymidylate synthase, have now been key cancer therapies for 60 years. In this article, the classic and novel approaches to targeting this metabolic pathway and strategies for overcoming drug resistance mechanisms are comprehensively reviewed. Over the past 60 years, chemotherapeutic agents that target thymidylate biosynthesis and the enzyme thymidylate synthase (TS) have remained among the most-successful drugs used in the treatment of cancer. Fluoropyrimidines, such as 5-fluorouracil and capecitabine, and antifolates, such as methotrexate and pemetrexed, induce a state of thymidylate deficiency and imbalances in the nucleotide pool that impair DNA replication and repair. TS-targeted agents are used to treat numerous solid and haematological malignancies, either alone or as foundational therapeutics in combination treatment regimens. We overview the pivotal discoveries that led to the rational development of thymidylate biosynthesis as a chemotherapeutic target, and highlight the crucial contribution of these advances to driving and accelerating drug development in the earliest era of cancer chemotherapy. The function of TS as well as the mechanisms and consequences of inhibition of this enzyme by structurally diverse classes of drugs with distinct mechanisms of action are also discussed. In addition, breakthroughs relating to TS-targeted therapies that transformed the clinical landscape in some of the most-difficult-to-treat cancers, such as pancreatic, colorectal and non-small-cell lung cancer, are highlighted. Finally, new therapeutic agents and novel mechanism-based strategies that promise to further exploit the vulnerabilities and target resistance mechanisms within the thymidylate biosynthesis pathway are reviewed.

Background HIV viral suppression is associated with health benefits for people living with HIV and a decreased risk of HIV transmission to others. The objective was to identify demographic, psychosocial, provider and neighborhood factors associated with sustained viral suppression among gay, bisexual, and other men who have sex with men. Methods Data from adult men who have sex with men (MSM) enrolled in the Miami-Dade County Ryan White Program (RWP) before 2017 were used. Sustained viral suppression was defined as having an HIV viral load < 200 copies/ml in all viral load tests in 2017. Three-level (individual, medical case management site, and neighborhood) cross-classified mixed-effect models were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for sustained viral suppression. Results Of 3386 MSM, 90.8% were racial/ethnic minorities, and 84.4% achieved sustained viral suppression. The odds of achieving sustained viral suppression was lower for 18–24 and 25–34 year-old MSM compared with 35–49 year-old MSM, and for non-Latino Black MSM compared with White MSM. Those not enrolled in the Affordable Care Act, and those with current AIDS symptoms and a history of AIDS had lower odds of achieving sustained viral suppression. Psychosocial factors significantly associated with lower odds of sustained viral suppression included drug/alcohol use, mental health symptoms, homelessness, and transportation to appointment needs. Individuals with an HIV physician who serves a larger volume of RWP clients had greater odds of sustained viral suppression. Neighborhood factors were not associated with sustained viral suppression. Conclusion Despite access to treatment, age and racial disparities in sustained viral suppression exist among MSM living with HIV. Addressing substance use, mental health, and social services’ needs may improve the ability of MSM to sustain viral suppression long-term. Furthermore, physician characteristics may be associated with HIV outcomes and should be explored further.

Despite advances in biomedical treatments, women living with HIV (WLH) who experience homelessness and housing instability suffer suboptimal HIV outcomes, even when linked to treatment. The purpose of this study was to explore experiences of housing instability among WLH and to understand its role in their ability to adhere to antiretroviral medication and remain retained in care. Sixteen women who were linked to Ryan White Program HIV care in South Florida participated in in-depth interviews. The findings focus around four larger themes: difficulty storing medication, privacy- and stigma-related issues, inconsistent access to medication and health care disruptions, and competing and unmet physical and mental health needs. Findings underscore the importance of strategies that are responsive to the disruption of routines and are sensitive to privacy issues in shared dwelling spaces; the proactive inquiry of behavioral and environmental considerations when prescribing antiretroviral medication; and the identification and treatment of comorbid conditions. This study provides evidence for strategies to facilitate self-management and improve modifiable system realities to augment larger-level policy and funding shifts that are critically needed to end the epidemic among vulnerable populations living with HIV.

Background People with HIV (PWH) from racial and ethnic minority groups in the United States (US) face a high risk for severe COVID-19 outcomes and have low uptake of the COVID-19 vaccine primary series and booster doses. This study aims to provide insights into barriers and facilitators to vaccination and identify strategies to increase vaccine trust and uptake in these populations. Methods Between November and December 2022, we conducted qualitative interviews with 24 vaccinated and unvaccinated adult PWH who self-identified as Hispanic/Latinx, Black/African American, or Haitian, and were clients of the Miami-Dade County Ryan White HIV/AIDS Program in Florida, US. Data were analyzed using deductive thematic analysis. Results Main barriers to vaccine uptake reported by participants included low or no perception of COVID-19 risk, concerns about safety and efficacy related to HIV status, mistrust of COVID-19 vaccines, general vaccine hesitancy, negative experiences and advice against vaccination within social networks, lack of provider recommendation, and exposure to negative messaging and misinformation about vaccines. Facilitators included perceived risk, awareness of the vaccines’ protective benefits for HIV-immunocompromised individuals and reducing transmission, encouragement and role modeling within social networks, provider recommendation, and exposure to accurate information from reputable sources. Some recommended strategies to increase uptake and trust in vaccines included incorporating vaccination into routine HIV care, leveraging peers with HIV, tailoring vaccine information and messaging, and partnering with trusted individuals for outreach. Conclusion Vaccination efforts for PWH should prioritize addressing specific barriers and concerns related to their HIV status and tailoring strategies to meet their needs.

The study’s objective was to examine variations in viral load (VL) suppression definitions among clients in the Ryan White Program (RWP). Data from clients enrolled in the RWP during 2017 were examined to calculate the proportion of virally suppressed clients using three definitions: recent viral suppression, defined as having a suppressed VL (< 200 copies/mL) in the last test in 2017; maintained viral suppression, having a suppressed VL for both the first and last tests in 2017; and sustained viral suppression, having all tests in 2017 showing suppression. Relative differences across all three definitions were computed. Recent viral suppression measures were higher than maintained and sustained viral suppression measures by 7.0% and 10.1%, respectively. Significant relative differences in definitions by demographic, socioeconomic and clinical status were observed. It may be beneficial for care planning to report not only estimates of recent viral suppression but maintained and sustained viral suppression as well.

Women with HIV (WWH) face increased difficulties maintaining adherence to antiretroviral therapy (ART) due to a variety of demographic and psychosocial factors. To navigate the complexities of ART regimens, use of strategies to maintain adherence is recommended. Research in this area, however, has largely focused on adherence interventions, and few studies have examined self-reported preferences for adherence strategies. The purpose and objectives of this study were to explore the use of ART self-management strategies among a diverse sample of WWH, examine demographic and psychosocial differences in strategy use, and assess the association between strategies and ART adherence. The current study presents secondary data of 560 WWH enrolled in the Miami-Dade County Ryan White Program. Participants responded to questionnaire items assessing demographic and psychosocial characteristics, use of adherence strategies, and ART adherence during the past month. Principal component analysis identified four categories among the individual strategies and multivariable binomial logistic regression assessed adherence while controlling for individual-level factors. The majority of WWH reported optimal ART adherence, and nearly all used multiple individual strategies. The number of individual strategies used and preferences for strategy types were associated with various demographic and psychosocial characteristics. Adjusting for demographic and psychosocial characteristics, optimal ART adherence during the past month was associated with the use of four or more individual strategies. When conducting regular assessments of adherence, it may be beneficial to also assess use of adherence strategies and to discuss with WWH how using multiple strategies contributes to better adherence.

Background Despite the significant progress made in colon cancer chemotherapy, advanced disease remains largely incurable and novel efficacious chemotherapies are urgently needed. Histone deacetylase inhibitors (HDACi) represent a novel class of agents which have demonstrated promising preclinical activity and are undergoing clinical evaluation in colon cancer. The goal of this study was to identify genes in colon cancer cells that are differentially regulated by two clinically advanced hydroxamic acid HDACi, vorinostat and LBH589 to provide rationale for novel drug combination partners and identify a core set of HDACi-regulated genes. Methods HCT116 and HT29 colon cancer cells were treated with LBH589 or vorinostat and growth inhibition, acetylation status and apoptosis were analyzed in response to treatment using MTS, Western blotting and flow cytometric analyses. In addition, gene expression was analyzed using the Illumina Human-6 V2 BeadChip array and Ingenuity ® Pathway Analysis. Results Treatment with either vorinostat or LBH589 rapidly induced histone acetylation, cell cycle arrest and inhibited the growth of both HCT116 and HT29 cells. Bioinformatic analysis of the microarray profiling revealed significant similarity in the genes altered in expression following treatment with the two HDACi tested within each cell line. However, analysis of genes that were altered in expression in the HCT116 and HT29 cells revealed cell-line-specific responses to HDACi treatment. In addition a core cassette of 11 genes modulated by both vorinostat and LBH589 were identified in both colon cancer cell lines analyzed. Conclusion This study identified HDACi-induced alterations in critical genes involved in nucleotide metabolism, angiogenesis, mitosis and cell survival which may represent potential intervention points for novel therapeutic combinations in colon cancer. This information will assist in the identification of novel pathways and targets that are modulated by HDACi, providing much-needed information on HDACi mechanism of action and providing rationale for novel drug combination partners. We identified a core signature of 11 genes which were modulated by both vorinostat and LBH589 in a similar manner in both cell lines. These core genes will assist in the development and validation of a common gene set which may represent a molecular signature of HDAC inhibition in colon cancer.

Background: Patient-centered care (PCC) improves HIV adherence and retention, though lack of consensus on its conceptualization and understanding how it is interpreted has hindered implementation. Methods: We recruited 20 HIV providers at Ryan White Programs in FL for in-depth interviews. Thematic analysis identified core consistencies pertaining to: 1) provider perceptions, 2) current practices promoting PCC. Results: Provider perceptions of PCC emerged under four domains: 1) holistic, 2) individualized care, 3) respect for comfort and security, and 4) patient engagement and partnership. PCC practices occurred at multiple levels: 1) individual psychosocial and logistical support, 2) interpersonal support within patient-provider relationships through respectful communication and active engagement, and 3) institutional practices including feedback mechanisms, service integration, patient convenience, and diverse staffing. Conclusions: Our findings highlight the central tenets of PCC as respectful, holistic, individualized, and engaging care. We offer an HIV-adapted framework of PCC as a multilevel construct to guide future intervention. Plain Language Summary Patient-centered care perspectives among HIV care providers This study explores HIV care provider perceptions of patient-centered care (PCC) by analyzing common themes that arose in interviews. We found that providers perceived PCC to be holistic, individualized care focused on respecting patient comfort and security and actively engaging them as partners in care. Providers discussed a variety of ways in which they practiced PCC at the individual service level through psychosocial and logistical support, through their interpersonal relationships with respectful communication and trust, and through more structured facility level policies and activities such as greater service integration and employing a diverse staff. PCC is rapidly becoming the new standard of care and this study hopes to offer insight into provider perceptions of PCC and examples of practice in the HIV care field.

Background Respect is essential to providing high quality healthcare, particularly for groups that are historically marginalized and stigmatized. While ethical principles taught to health professionals focus on patient autonomy as the object of respect for persons, limited studies explore patients’ views of respect. The purpose of this study was to explore the perspectives of a multiculturally diverse group of low-income women living with HIV (WLH) regarding their experience of respect from their medical physicians. Methods We analyzed 57 semi-structured interviews conducted at HIV case management sites in South Florida as part of a larger qualitative study that explored practices facilitating retention and adherence in care. Women were eligible to participate if they identified as African American ( n  = 28), Hispanic/Latina ( n  = 22), or Haitian ( n  = 7). They were asked to describe instances when they were treated with respect by their medical physicians. Interviews were conducted by a fluent research interviewer in either English, Spanish, or Haitian Creole, depending on participant’s language preference. Transcripts were translated, back-translated and reviewed in entirety for any statements or comments about “respect.” After independent coding by 3 investigators, we used a consensual thematic analysis approach to determine themes. Results Results from this study grouped into two overarching classifications: respect manifested in physicians’ orientation towards the patient (i.e., interpersonal behaviors in interactions) and respect in medical professionalism (i.e., clinic procedures and practices). Four main themes emerged regarding respect in provider’s orientation towards the patient: being treated as a person, treated as an equal, treated without blame or prejudice, and treated with concern/emotional support. Two main themes emerged regarding respect as evidenced in medical professionalism: physician availability and considerations of privacy. Conclusions Findings suggest a more robust conception of what ‘respect for persons’ entails in medical ethics for a diverse group of low-income women living with HIV. Findings have implications for broadening areas of focus of future bioethics education, training, and research to include components of interpersonal relationship development, communication, and clinic procedures. We suggest these areas of training may increase respectful medical care experiences and potentially serve to influence persistent and known social and structural determinants of health through provider interactions and health care delivery.

The study’s objective was to identify the association between sustained viral suppression (all viral load tests < 200 copies/ml per year) and patterns of co-occurring risk factors including, mental health, substance use, sexual risk behavior, and adverse social conditions for people with HIV (PWH). Latent class analysis followed by multivariable logistic regression was conducted for 6554 PWH in the Miami-Dade County Ryan White Program during 2017, and a five-class model was selected. Compared to Class 1 (no risk factors), the odds of achieving sustained viral suppression was significantly lower for Class 2 (mental health) (aOR: 0.67; 95% CI 0.54–0.83), Class 3 (substance use and multiple sexual partners) (0.60; 0.47–0.76), Class 4 (substance use, multiple sexual partners, and domestic violence) (0.71; 0.55–0.93), and Class 5 (mental health, substance use, multiple sexual partners, domestic violence, and homelessness) (0.26; 0.19–0.35). Findings indicate the need for targeted interventions that address these syndemic factors.