Elimination Targets Research Articles

Mortality and morbidity related to hepatitis C virus infection in hospitalized adults-A propensity score matched analysis.

The World Health Organization (WHO) aims to reduce HCV mortality, but estimates are difficult to obtain. We aimed to identify electronic health records of individuals with HCV infection, and assess mortality and morbidity. We applied electronic phenotyping strategies on routinely collected data from patients hospitalized at a tertiary referral hospital in Switzerland between 2009 and 2017. Individuals with HCV infection were identified using International Classification of Disease (ICD)-10 codes, prescribed medications and laboratory results (antibody, PCR, antigen or genotype test). Controls were selected using propensity score methods (matching by age, sex, intravenous drug use, alcohol abuse and HIV co-infection). Main outcomes were in-hospital mortality and attributable mortality (in HCV cases and study population). The non-matched dataset included records from 165,972 individuals (287,255 hospital stays). Electronic phenotyping identified 2285 stays with evidence of HCV infection (1677 individuals). Propensity score matching yielded 6855 stays (2285 with HCV, 4570 controls). In-hospital mortality was higher in HCV cases (RR 2.10, 95%CI 1.64 to 2.70). Among those infected, 52.5% of the deaths were attributable to HCV (95%CI 38.9 to 63.1). When cases were matched, the fraction of deaths attributable to HCV was 26.9% (HCV prevalence: 33%), whilst in the non-matched dataset, it was 0.92% (HCV prevalence: 0.8%). In this study, HCV infection was strongly associated with increased mortality. Our methodology may be used to monitor the efforts towards meeting the WHO elimination targets and underline the importance of electronic cohorts as a basis for national longitudinal surveillance.

Evaluating the availability and quality of services for lymphatic filariasis morbidity in Ghana.

In districts where lymphatic filariasis (LF) is endemic, the goal is to provide 100% geographical coverage of the essential package of care. Additionally, countries seeking elimination status must document the availability of services for lymphoedema and hydrocele in all endemic areas. To do this, the WHO recommends conducting assessments of the readiness and quality of services provided to identify service delivery and quality gaps. This study used the recommended WHO Direct Inspection Protocol (DIP), which consists of 14 core indicators related to LF case management, medicine and commodities, staff knowledge and patient tracking. The survey was administered in 156 health facilities across Ghana designated and trained to provide LF morbidity management services. Patient and health provider interviews were also conducted to assess challenges and feedback. The highest performing indicators across the 156 surveyed facilities were related to staff knowledge; 96.6% of health workers correctly identified two or more signs and symptoms. The lowest scoring indicators concerned medication availability, with the two lowest scoring indicators in the survey being availability of antifungals (26.28%) and antiseptics (31.41%). Hospitals performed best with an overall score of 79.9%, followed by health centers (73%), clinics (67.1%) and CHPS compounds (66.8%). The most commonly reported challenge from health worker interviews was lack of medications and supplies, followed by a lack of training or poor motivation. The findings from this study can help the Ghana NTD Program identify areas of improvement as they seek to achieve LF elimination targets and continue to improve access to care for those with LF-related morbidity as part of overall health systems strengthening. Key recommendations include prioritizing refresher and MMDP training for health workers, ensuring reliable patient tracking systems, and integrating lymphatic filariasis morbidity management into the routine healthcare system to ensure medicine and commodity availably.

Hepatitis C treatment uptake among people who inject drugs in Oslo, Norway: A registry-based study.

Improving HCV treatment uptake among people who inject drugs (PWID) is crucial to achieving the WHO elimination targets. The aims were to evaluate HCV treatment uptake and HCV RNA prevalence in a large cohort of PWID in Norway. Registry-based observational study where all users of the City of Oslo's low-threshold social and health services for PWID between 2010-2016 (n=5330) were linked to HCV notifications (1990-2019) and dispensions of HCV treatment, opioid agonist treatment (OAT) and benzodiazepines (2004-2019). Cases were weighted to account for spontaneous HCV clearance. Treatment rates were calculated using person-time of observation, and factors associated with treatment uptake were analysed using logistic regression. HCV RNA prevalence was estimated among individuals alive by the end of 2019. Among 2436 participants with chronic HCV infection (mean age 46.8 years, 30.7% female, 73.3% OAT), 1118 (45.9%) had received HCV treatment between 2010-2019 (88.7% DAA-based). Treatment rates increased from 1.4/100 PY (95% CI 1.1-1.8) in the pre-DAA period (2010-2013) to 3.5/100 PY (95% CI 3.0-4.0) in the early DAA period (2014-2016; fibrosis restrictions) and 18.4/100 PY (95% CI 17.2-19.7) in the late DAA period (2017-2019; no restrictions). Treatment rates for 2018 and 2019 exceeded a previously modelled elimination threshold of 50/1000 PWID. Treatment uptake was less likely among women (aOR 0.74; 95% CI 0.62-0.89) and those aged 40-49 years (aOR 0.74; 95% CI 0.56-0.97), and more likely among participants with current OAT (aOR 1.21; 95% CI 1.01-1.45). The estimated HCV RNA prevalence by the end of 2019 was 23.6% (95% CI 22.3-24.9). Although HCV treatment uptake among PWID increased, strategies to improve treatment among women and individuals not engaged in OAT should be addressed.

FRI-180 - Hepatitis C seroprevalence screening and linkage to care of unknown infected patients admitted to a tertiary care emergency departement: on the road to achieve the WHO 2030 virus elimination target

FRI-180 - Hepatitis C seroprevalence screening and linkage to care of unknown infected patients admitted to a tertiary care emergency departement: on the road to achieve the WHO 2030 virus elimination target

A population-level application of a method for estimating the timing of HIV acquisition among migrants to Australia.

Australia has set the goal for the virtual elimination of HIV transmission by the end of 2022, yet accurate information is lacking on the level of HIV transmission occurring among residents. We developed a method for estimating the timing of HIV acquisition among migrants, relative to their arrival in Australia. We then applied this method to surveillance data from the Australian National HIV Registry with the aim of ascertaining the level of HIV transmission among migrants to Australia occurring before and after migration, and to inform appropriate local public health interventions. We developed an algorithm incorporating CD4+ T-cell decline back-projection and enhanced variables (clinical presentation, past HIV testing history and clinician estimate of the place of HIV acquisition) and compared it to a standard algorithm which uses CD4+ T-cell back-projection only. We applied both algorithms to all new HIV diagnoses among migrants to estimate whether HIV infection occurred before or after arrival in Australia. Between 1 January 2016 and 31 December 2020, 1909 migrants were newly diagnosed with HIV in Australia, 85% were men, and the median age was 33 years. Using the enhanced algorithm, 932 (49%) were estimated to have acquired HIV after arrival in Australia, 629 (33%) before arrival (from overseas), 250 (13%) close to arrival and 98 (5%) were unable to be classified. Using the standard algorithm, 622 (33%) were estimated to have acquired HIV in Australia, 472 (25%) before arrival, 321 (17%) close to arrival and 494 (26%) were unable to be classified. Using our algorithm, close to half of migrants diagnosed with HIV were estimated to have acquired HIV after arrival in Australia, highlighting the need for tailored culturally appropriate testing and prevention programmes to limit HIV transmission and achieve elimination targets. Our method reduced the proportion of HIV cases unable to be classified and can be adopted in other countries with similar HIV surveillance protocols, to inform epidemiology and elimination efforts.

FRI-115 - An international coalition to eliminate hepatitis B virus (ICE-HBV) survey confirms inadequate HBV/HDV screening and diagnosis diminishing elimination targets in resource limited settings

FRI-115 - An international coalition to eliminate hepatitis B virus (ICE-HBV) survey confirms inadequate HBV/HDV screening and diagnosis diminishing elimination targets in resource limited settings

The impact of immigration on hepatitis B burden in the United States: a modelling study

The 2016 World Health Assembly endorsed the elimination of hepatitis B virus (HBV) infections by 2030. However, the HBV prevalence in Western countries, where the historical prevalence is low and highly impacted by immigration trends, remains uncertain making planning difficult. We aimed to develop a more accurate estimate of HBV prevalence and identify key immigrant populations that need to be screened, vaccinated, and treated to achieve the elimination targets. US immigration data from 1900 forward and country-specific modeled prevalence by age and sex were used to estimate immigrated HBV infections entering the US, new infections in the US, mortality (all-cause and liver-related), and disease burden through2030. Using a dynamic Markov model, we estimated 1.8 million (95% uncertainty interval: 1.3-2.6 million) HBV infections in 2020 in all ages, higher than the NHANES national serosurvey. Infections between ages 30-74 accounted for 82% of all cases. Furthermore, HBV infections were concentrated among immigrants. New decompensated cirrhosis, hepatocellular carcinoma, and liver related deaths are expected to increase by 20%, 31% and 25% respectively from 2019 to 2030at current diagnosis and treatment rate. National serosurveys can underestimate total infections due to under-sampling in immigrant populations. To meet the WHO elimination targets, culturally appropriate screening and linkage to care programs in the immigrant populations are needed in the US. In their absence, there will be significant increases in the burden of HBV and the US will fail to meet the elimination targets by2030. This analysis was funded by a research grant from Gilead Sciences (IN-US-988-5786) and made possible by grants from John C Martin Foundation (2019-G024), ZeShan Foundation (2021-0101-1-CDA-HEP-10), and EndHep2030 who supported country analyses.

Lymphatic filariasis endgame strategies: Using GEOFIL to model mass drug administration and targeted surveillance and treatment strategies in American Samoa.

American Samoa underwent seven rounds of mass drug administration (MDA) for lymphatic filariasis (LF) from 2000-2006, but subsequent surveys found evidence of ongoing transmission. American Samoa has since undergone further rounds of MDA in 2018, 2019, and 2021; however, recent surveys indicate that transmission is still ongoing. GEOFIL, a spatially-explicit agent-based LF model, was used to compare the effectiveness of territory-wide triple-drug MDA (3D-MDA) with targeted surveillance and treatment strategies. Both approaches relied on treatment with ivermectin, diethylcarbamazine, and albendazole. We simulated three levels of whole population coverage for 3D-MDA: 65%, 73%, and 85%, while the targeted strategies relied on surveillance in schools, workplaces, and households, followed by targeted treatment. In the household-based strategies, we simulated 1-5 teams travelling village-to-village and offering antigen (Ag) testing to randomly selected households in each village. If an Ag-positive person was identified, treatment was offered to members of all households within 100m-1km of the positive case. All simulated interventions were finished by 2027 and their effectiveness was judged by their 'control probability'-the proportion of simulations in which microfilariae prevalence decreased between 2030 and 2035. Without future intervention, we predict Ag prevalence will rebound. With 3D-MDA, a 90% control probability required an estimated ≥ 4 further rounds with 65% coverage, ≥ 3 rounds with 73% coverage, or ≥ 2 rounds with 85% coverage. While household-based strategies were substantially more testing-intensive than 3D-MDA, they could offer comparable control probabilities with substantially fewer treatments; e.g. three teams aiming to test 50% of households and offering treatment to a 500m radius had approximately the same control probability as three rounds of 73% 3D-MDA, but used < 40% the number of treatments. School- and workplace-based interventions proved ineffective. Regardless of strategy, reducing Ag prevalence below the 1% target threshold recommended by the World Health Organization was a poor indicator of the interruption of LF transmission, highlighting the need to review blanket elimination targets.

Characteristics of the receptor phenotype of tumor-associated immune cells of the epithelial-mesenchymal microenvironment of ovarian cancer

Among all histological types, serous carcinomas account for up to 85%. Due to pronounced heterogeneity (at the molecular and genetic level) and chemoresistance, difficulties arise in finding active targets for tumor elimination.&#x0D; Aim. To establish a link between the population composition of tumor-associated immune cells of the microenvironment and the stage of serous ovarian cancer.&#x0D; Materials and methods. The analysis of the pathologic and anatomical material in 74 patients with serous ovarian cancer was carried out. Monoclonal antibodies were used to determine antigens in the samples: CD3, CD4, CD8, CD11b, CD14 and CD16.&#x0D; Results. The obtained results of the immunohistochemical study showed that in the composition of the immune cells of the microenvironment, the largest number of cells, at all stages (IIV) of the oncological process, are represented by macrophages (CD11b+, CD14+), CD3+ lymphocytes are in second place in terms of the number of cells, followed by CD8+ and CD4+ and the smallest number of CD16+ cells.&#x0D; Conclusion. As a result of the immunohistochemical study, a multidirectional trend was found between the population composition of tumor-associated immune cells of the microenvironment and the stage of serous ovarian cancer. With an increase in the stage of the disease, the number of macrophages (CD11b+, CD14+) and lymphocytes (CD3+, CD16+) decreased regardless of the degree of differentiation of the tumor. With an increase in the tumor stage, the number of CD4+ and CD8+ populations decreased, but in this case, the degree of differentiation played a significant role, i.e. the higher the tumor stage and the lower the degree of differentiation, the fewer cells were detected.

Current Status of Leprosy in the Rural Area of North Gresik, Indonesia After Eliminated Status Achieved: “Is Leprosy Truly Eliminated?”

Introduction: This study aims to provide the current situation of leprosy prevalence and clinical findings in one of the endemic regions of North Gresik City that has already achieved elimination status. Leprosy remains a public health problem in some developing countries, including Indonesia. Indonesia, with two other big countries, India and Brazil, contributed 74% of all the new leprosy cases detected. Even though Indonesia achieved the elimination target from WHO in 2018, the endemic pockets are still scattered, and new cases remain detected each year. Methods: This study is a one-decade retrospective analysis descriptive record based on newly diagnosed cases of leprosy from 2010 until 2020. We use total data sampling of all newly diagnosed leprosy cases and analyze using SPSS. Result: This study found that newly diagnosed cases of leprosy are still discovered each year. 15.7% of newly diagnosed cases were children. MB type was dominated type in this study. MB types are statistically significant in male subjects (35.5%) diagnosed more than one year after the symptoms appear. 40.7% were found with deformity when first diagnosed. Conclusion: This study reports a high rate of contracting leprosy disease in children, with 15.7% of cases. It indicates that disease transmission remains high in the community and might be out of control. The new cases diagnosed dominated with MB type, and 40.7% had deformity when first diagnosed. There was a delayed diagnosis reported that could be caused by ineffective surveillance for early diagnosing new cases.

Low attendance in cervical cancer screening, geographical disparities and sociodemographic determinants of screening uptake among adult women in Burkina Faso : results from the first nationwide population-based survey

ObjectiveTo explore the level, geographical disparities and sociodemographic determinants of cervical cancer screening uptake among adult women in Burkina Faso by using data from the first national population-based survey. MethodsThis was a cross-sectional secondary analysis of primary data obtained by the 2013 World Health Organization (WHO) Stepwise Approach to Surveillance survey conducted in Burkina Faso. All 13 Burkinabè regions, with their different rates of urbanization, were surveyed. Lifetime cervical cancer screening uptake was explored. We included 2293 adult women for analyses and performed Student's t, chi-square and Fisher's exact tests, and logistic regression. ResultsOnly 6.2% (95% CI: 5.3–7.3) of women had ever been screened for cervical cancer. For two regions (“Centre” and “Hauts-Bassins”), the pooled frequency was 16.6% (95% CI: 13.5–20.1) while in the other eleven regions it was significantly lower, 3.3% (95% CI: 2.5–4.2). In urban and rural areas, the respective frequencies for the screening uptake were 18.5% and 2.8% (p < 0.001), and in educated and un-educated women, frequencies were 27.7% and 3.3% (p < 0.001) respectively. The sociodemographic factors associated with screening uptake were being educated (adjusted odd-ratio [aOR] = 4.3; 95% CI: 2.8–6.7), urban residence (aOR = 3.8, 95% CI: 2.5–5.8) and having an occupation providing income (aOR = 3.1, 95% CI: 1.8–5.4). ConclusionThere was a significantly wide range in screening uptake between Burkina Faso regions, and the overall national as well as the region-specific levels were far below the WHO's target for cervical cancer elimination. Cervical cancer interventions should be tailored specifically for Burkinabè women with different educational levels, and prevention strategies based on community engagement integrating psychosocial considerations could be helpful.

Assessing the potential cost-effectiveness of centralised versus point-of-care testing for hepatitis C virus in Pakistan: a model-based comparison

ObjectivesPakistan has a hepatitis C virus (HCV) infection prevalence of 6%–9% and aims to achieve World Health Organisation (WHO) targets for elimination of HCV by the year 2030. We aim...

Wolbachia Ferrochelatase as a potential drug target against filarial infections

Filarial infections are among the world's most disturbing diseases caused by 3 major parasitic worms; Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi, affecting more than 500 million people worldwide. Currently used drugs for mass drug administration (MDA) have been met with several challenges including the development of complications in individuals with filaria co-infections and parasitic drug resistance. The filarial endosymbiont, Wolbachia, has emerged as an attractive therapeutic target for filariasis elimination, due to the dependence of the filaria on this endosymbiont for survival. Here, we target an important enzyme in the Wolbachia heme biosynthetic pathway (ferrochelatase), using high-throughput virtual screening and molecular dynamics with MM-PBSA calculations. We identified four drug candidates; Nilotinib, Ledipasvir, 3-benzhydryloxy-8-methyl-8-azabicyclo[3.2.1]octane, and 2-(4-Amino-piperidin-1-yl)-ethanol as potential small molecules inhibitors as they could compete with the enzyme's natural substrate (Protoporphyrin IX) for active pocket binding. This prevents the worm from receiving the heme molecule from Wolbachia for their growth and survival, resulting in their death. This study which involved targeting enzymes in biosynthetic pathways of the parasitic worms' endosymbiont (Wolbachia), has proven to be an alternative therapeutic option leading to the discovery of new drugs, which will help facilitate the elimination of parasitic infections.

Health and economic impact of delaying large-scale HPV vaccination and screening implementation on cervical cancer in China: a modelling study

Current uptake of HPV vaccination and screening in China is far below World Health Organization 2030 targets for cervical cancer elimination. We quantified health and economic losses of delaying large-scale HPV vaccination and screening implementation in China. We used a previously validated transmission model to project lifetime health benefits, costs, effectiveness, and timeline for cervical cancer elimination of alternative scenarios, including combining HPV vaccination initiated from 2022 to 2030 with screening in different modalities and coverage increase rates, as well as screening alone. All women living or projected to be born in China during 2022-2100 were considered. We employed a societal perspective. Regardless of vaccine type, immediate large-scale vaccination initiated in 2022 and achieving 70% coverage of HPV-based screening in 2030 (no-delay scenario) would be the least costly and most effective. Compared with the no-delay scenario, delaying vaccination by eight years would result in 434,000-543,000 additional cervical cancer cases, 138,000-178,000 deaths, and $2863-4437 million costs, and delay elimination by 9-10 years. Even with immediate vaccination, the gradual scale-up of LBC-based screening to 70% coverage in 2070 would result in 2,530,000-3,060,000 additional cases, 909,000-1,040,000 deaths, and $5098-5714 million costs compared with no-delay scenario, and could not achieve elimination if domestic 2vHPV or 4vHPV vaccines are used (4.09-4.21 cases per 100,000 woman in 2100). Delaying large-scale HPV vaccination and/or high-performance screening implementation has detrimental consequences for cervical cancer morbidity, mortality, and expenditure. These findings should spur health authorities to expedite large-scale vaccine rollout and improve screening. Bill & Melinda Gates Foundation (INV-031449 and INV-003174) and CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-004).

Investigating rates and risk factors for hepatitis C virus reinfection in people receiving antiviral treatment in England.

England has committed to the World Health Organization target to eliminate hepatitis C virus (HCV) as a public threat by the year 2030. Given successful treatments for HCV in recent years, it is unclear whether HCV reinfection will impact England's ability to achieve HCV elimination. We aimed to estimate the HCV reinfection rate among a cohort of patients receiving antiviral treatment using available surveillance data. Linkage between a treatment dataset from 2015 to 2019 and an HCV RNA testing dataset were used to identify people who experienced reinfection using three criteria. A Cox proportional hazards model was used to determine risk factors associated with HCV reinfection among a cohort who received treatment and had follow-up HCV RNA testing. The reinfection rate among those receiving HCV treatment was 7.91 per 100 person-years (PYs, 95% confidence interval (CI) 7.37-8.49) and highest among current injecting drug users (22.55 per 100 PYs, 95% CI 19.98-25.46) and people who had been in prison (20.42 per 100 PYs, 95% CI 17.21-24.24). In the adjusted model, women had a significantly reduced risk of reinfection. Being of younger age, current injecting drug users, and receipt of first treatment in prison were each significantly associated with increased risk of reinfection. Two-fifths of those with reinfection (43%, n=329/767) were linked to treatment after reinfection, and of those starting treatment, three quarters (75%, n=222/296) achieved a sustained virologic response. Guidance for testing groups at risk of reinfection and harm reduction strategies to minimize transmission should be implemented if England is to achieve HCV elimination targets.

Social Network Analysis of the Schistosomiasis control program in two local government areas in Oyo state, Nigeria: Insights for NTD elimination plans.

Schistosomiasis is one of the neglected tropical diseases targeted for elimination by 2030. Achieving disease elimination requires collaboration between stakeholders, country ownership and the involvement of community-level stakeholders. The state of stakeholder relationship determines the ease and timeliness of meeting disease elimination targets. Mapping stakeholder relationships is critical for assessing gaps in the schistosomiasis control program implementation, and providing a roadmap for improved stakeholder cohesion. The study aimed to measure the cohesiveness of the contact, collaboration and resource-sharing networks, across 2 local government areas in Oyo state, Nigeria. This study used a Network Representative design for Social Network Analysis (SNA). The study was conducted within Oyo state, Nigeria using 2 Local Government Areas (LGAs): Ibadan North (urban) and Akinyele (rural). Stakeholders were identified using a link-tracing approach. Data was collected using Qualtrics software from stakeholders across the state, local government, healthcare, academia, and non-governmental organizations. Data was analysed using Gephi software for network cohesion across the three networks. The social network analysis revealed high clustering and low density across the three networks implying low cohesion across multiple stakeholder categories. The contact and collaborative networks were the most active with the lowest level of cohesion seen in the resource-sharing network. Stakeholders were more active in the rural LGA than the urban, and stakeholders within the organized governance and public health system were the dominant actors in the schistosomiasis control program. The low cohesion, high clustering and low network density among stakeholders within the schistosomiasis control program should be addressed in other to drive innovation and meet the WHO schistosomiasis elimination target.

Incidence of HIV Infection among HIV-Exposed Iinfants at Gondar University Hospital from 2019-2021: A Prospective Cohort Study.

Mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) is decreasing worldwide; however, achieving the MTCT elimination target of 2% by 2020 and 0% by 2030 is challenging in resource-limited countries. Preventing mother-to-child transmission (PMTCT) is a key strategy in eliminating new pediatric human immunodeficiency virus (HIV) infection Strengthening PMTCT program is one of the key mechanisms for the elimination of Pediatric HIV infection and improving maternal and newborn survival. Assessing the incidence of HIV infection among HIV exposed infants is critical to devise an important preventive strategy which was the main objective of this study. A prospective Cohort study was conducted at Gondar University Comprehensive Specialized Hospital, PMTCT clinic to assess the incidence of HIV infection among HIV exposed infants from 2019-2021. The overall incidence of HIV infection among HIV exposed infants was 3.6%. HIV infection rate was significantly increased among HIV exposed infants coming out of Gondar, Infants with developmental failure and Infants with Unknown fathers' HIV status compared to their counterpart. The incidence of HIV infection among 307 HIV-exposed infants was 3.6% which is higher than the expected standard. The lost to follow up rate was also significant (9.4%). These finding showed that strengthening the PMCT service is mandatory.

Abstract 1493: ROS inhibits enzymatic activation of PRMT5 and increases the protein stability of tumor suppressors as non-histone substrates in liver cancer

Abstract Retinoic acid receptor-related orphan receptor α (RORα) and p53 are transcription factors involved in nuclear gene expression and known tumor suppressors. RORα was the first identified substrate of lysine methylation-dependent degradation. However, the mechanisms of other post-translational modifications (PTMs) that occur in RORα and p53 remain largely unknown, especially in liver cancer. Arginine methylation is a common PTM in arginine residues of nonhistone and histone proteins and affects substrate protein function and fate. We found an analogous amino acid disposition containing R37 at the ROR N-terminus compared to histone H3 residue, which is arginine methylated. Here, we provide evidence that R37 methylation-dependent degradation is carried out by protein arginine methyltransferase 5 (PRMT5). In addition, we discovered that PRMT5 regulated the interaction between the E3 ubiquitin ligase ITCH and RORα through RORα arginine methylation. Arginine methylation-dependent ubiquitination-mediated RORα degradation reduced downstream target gene activation. H2O2-induced reactive oxygen species (ROS) decreased PRMT5 protein levels, consequently increasing RORα protein levels in liver cancer in vitro and in vivo. Furthermore, the enzymatic activities of PRMT5 were directly affected by ROS via the dissociation of PRMT5-Mep50 octamer in the methylosome complex. Taken together, ROS inhibited liver cancer progression by inducing apoptosis via PRMT5-mediated methylation of RORα combined with other histone and non-histone substrates and the ITCH axis. Our results potentiate PRMT5 as an elimination target in cancer therapy, and this additional regulatory level within ROS signaling may help identify new targets for therapeutic intervention in liver cancer. Citation Format: Ji Min Lee, Hyunkyung Kim, Hyuntae Im, Hee-ji Baek. ROS inhibits enzymatic activation of PRMT5 and increases the protein stability of tumor suppressors as non-histone substrates in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1493.

Abstract 4969: Enhancing the efficacy of small molecule inhibitor of TRIP13 in prostate cancer using thymoquinone

Abstract Prostate cancer (PCa) is one of the leading causes of cancer-related death in men worldwide. Chemotherapy is effective in the early management of PCa; long-term use activates drug efflux pumps, resulting in resistance and recurrence. In this context, finding the genetic changes causing PCa development could significantly alter therapeutic results. The approach has been to search for specific molecular targets for the selective elimination of cancer cells. Small molecule inhibitor drugs have successfully targeted cancer cell growth and metastasis promotion. Still, small molecule inhibitors bind to multiple molecular targets, including cell surface receptors and other intracellular proteins, thus increasing the risk of toxicity and having a short life span. Therefore, it is crucial to identify new anti-cancer agents that work with small molecule inhibitors to target cancer cells while preventing normal cells. It has been reported that overexpression of the Thyroid hormone receptor interactor 13 (TRIP13) gene, a critical mitosis regulator, plays a role in many cancers. Our analysis using UALCAN (ualcan.path.uab.edu) showed overexpression of TRIP13 in PCa and it plays a role in PCa biology. When TRIP13 is overexpressed, it phosphorylates EGFR and activates a downstream pathway, making cancer cells more aggressive. Recently, DCZ0415, a small molecule TRIP13 inhibitor, was reported to prevent cell proliferation and invasion in several malignancies. Nevertheless, the therapeutic targeting of TRIP13 driving PCa is not well understood. In this study, we demonstrated Thymoquinone (TQ), a natural compound with multifaceted chemo-preventive potential and anti-cancer agent, could reinforce the effect of DCZ0415 in PCa cell lines (DU145 and PC3). PCa cells were treated with TQ or DCZ0415 alone or combined, followed by cell viability (MTT assay) to determine the optimal IC50 values. In a western blot, RT-qPCR analysis, and flow cytometry assays, the combined drug treatment was most effective in blocking TRIP13, inhibiting cell proliferation, and inducing apoptosis. Furthermore, this study determines the combination can upregulate the expression of cell cycle inhibitor (p21WAF1/CIP1), which, in turn, inhibits the expression of CDK4/Cyclin D1 complex, resulting the cell cycle arrest. In addition, TQ, in combination, downregulates the activation of EGFR-dependent PI3K/Akt-1/ERK1/2 and epithelial-mesenchymal transition (EMT) pathways in both cell lines. In conclusion, these findings show thymoquinone's potential to improve DCZ0415 effectiveness and suggest a new promising anti-cancer strategy for treating patients with prostate cancer. Citation Format: Santosh K. Singh, Manoj K. Mishra, Sooryanarayana Varambally, Rajesh Singh. Enhancing the efficacy of small molecule inhibitor of TRIP13 in prostate cancer using thymoquinone. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4969.

Abstract 2914: iPSC-derived CAR-NK cell therapy: nominating clinical candidate clones through integrated multi-functional analysis

Abstract CNTY-101 is an induced Pluripotent Stem Cell (iPSC) derived Chimeric Antigen Receptor (CAR) NK cell clinical candidate for the treatment of B-cell malignancies. It incorporates six gene edits. A CAR targeting CD19 mediates tumor cell engagement and killing, the homeostatic cytokine IL-15 improves functional persistence, and EGFR acts as a safety switch, providing an antibody target for elimination of the engineered cells, if ever necessary. Further edits are designed to reduce graft rejection due to alloreactivity, including disruption of beta-2-microglobulin (B2M) to prevent major histocompatibility complex class I (MHC-I) surface expression, disruption of class II major histocompatibility complex transactivator (CIITA), and expression of HLA-E fused with B2M. Our data indicate that iPSC lines show significant functional variability dependent on the original somatic cell and donor used for reprogramming. Additional functional variability is induced when the iPSC are genetically edited and differentiated to NK cells. This complexity necessitates careful methodology for nominating clinical candidate clones with desirable functional attributes and presents an opportunity for future refinement. Here, we evaluate 28 clinical candidate clones for CNTY-101, integrating in-process data from genetic engineering, differentiation, and a battery of functional assays into a unified analysis framework. We find that the donor and the number of integrated transgene alleles (ex. monoallelic vs biallelic) have a large impact on clone function. In silico correction for donor and allele number reveals that transgene surface expression correlates with functions including short-term killing, serial-killing, and persistence. We show that IL-15 transgene expression, serial-killing, and persistence correlate along one functional axis, while CAR expression, short-term killing, and cytokine secretion correlate on a second functional axis. In addition, we identify biomarkers measured during the differentiation process that are correlated with functional performance, such as the level of CD94 surface expression and tumor killing. Finally, we discuss the application of functional multi-omics to candidate clone nomination for Century Therapeutics’ pipeline of future products. Citation Format: Matthew S. Hall, Ohad Manor, Liam Campion, Chiamin Bullaughey, Barry A. Morse, Buddha Gurung, Luis Borges. iPSC-derived CAR-NK cell therapy: nominating clinical candidate clones through integrated multi-functional analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2914.