tbuckley/cabot-search huggingface dataset:
Lifetime effects and cost-effectiveness of standard and higher-intensity statin therapy across population categories in the UK: a microsimulation modelling study
Authors: Borislava Mihaylova, Runguo Wu, Junwen Zhou, Claire Williams, Iryna Schlackow, Jonathan Emberson, Christina Reith, Anthony Keech, John Robson, Richard Parnell, Jane Armitage, Alastair Gray, John Simes, Colin Baigent
Journal: The Lancet Regional Health - Europe (2024)

SummaryBackgroundCardiovascular disease incidence and mortality have declined across developed economies and granular up-to-date cost-effectiveness evidence is required for treatments targeting large populations. To assess the health benefits and cost-effectiveness of standard and higher intensity statin therapy in the contemporary UK population 40–70 years old.MethodsA cardiovascular disease microsimulation model, developed using the Cholesterol Treatment Trialists' Collaboration data (117,896 participants; 5 years follow-up), and calibrated in the UK Biobank cohort (501,854 participants; 9 years follow-up), projected risks of myocardial infarction, stroke, coronary revascularization, diabetes, cancer and vascular and nonvascular death for all UK Biobank participants without and with statin treatment. Meta-analyses of trials and cohort studies informed statins' relative effects on cardiovascular events, incident diabetes, myopathy and rhabdomyolysis. UK healthcare perspective was taken (2020/2021 UK£) with costs per 28 tablets of £1.10 for standard (35%–45% LDL cholesterol (LDL-C) reduction) and £1.68 for higher intensity (≥45% LDL-C reduction) generic statin.FindingsAcross categories by sex, age, LDL-C, and cardiovascular disease history/10-year cardiovascular risk, lifetime standard statin increased survival by 0.28–1.85 years (0.20–1.09 quality-adjusted life years (QALYs)), and higher intensity statin by further 0.06–0.40 years (0.03–0.20 QALYs) per person. Standard statin was cost-effective across all categories with incremental cost per QALY from £280 to £8530, with higher intensity statin cost-effective at higher cardiovascular risks and higher LDL-C levels. Stopping statin early reduced benefits and was not cost-effective.InterpretationLifetime low-cost statin therapy is cost-effective across all 40–70 years old in UK. Strengthening and widening statin treatment could cost-effectively improve population health.FundingUK NIHR Health Technology Assessment Programme (17/140/02).
Abstract 4382: PKC-ι/ζ signaling is crucial for apoptosis/pyroptosis inhibition and invasiveness of glioblastoma cells through upregulation of β-catenin, PDK1/Akt1 and Smad cascades via 14-3-3
Authors: Luke Lajmi, Wishrawana S. Ratnayake, Khandker M. Khalid, Sloan Breedy, Aaron Todman, Tracess Smalley, Christopher A. Apostolatos, Robert Hill, Mildred Acevedo-Duncan
Journal: Cancer Research (2024)

Abstract Glioblastoma (GB) is an aggressive form of brain cancer derived from astrocytes. Poor predictability of patient outcomes has limited the development of current therapeutic treatments of GB mainly due to the development of drug resistance. Comparative over-expression of atypical protein kinase C-iota and zeta (aPKC-ι/ζ) in GB cells and tissue samples were previously reported. This study establishes the downstream effects of PKC-ι/ζ attenuation on key cellular signaling which governs apoptosis, pyroptosis, survival, proliferation and epithelial-mesenchymal transition (EMT). Our data suggested that aPKC knockdown of expression induces apoptosis and works as an antecedent of pyroptosis. Data also suggested that involvement of Akt1 and PDK1 in aPKC maturation process weakened due to aPKC attenuation. aPKC attenuation downregulated Ras/Erk1 and canonical β-catenin pathways which resulted in reduced transcriptional activities of Stat3, c-Myc, c-Jun and β-catenin. In addition SNAIL1, SLUG, and PRRX1 were diminished that have been known to stimulate EMT. Proteins 14-3-3 and Smad2/3 acted as molecular adaptors between these pathways. A PKC-ι specific inhibitor 5-amino-1-(2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and a PKC-ζ specific inhibitor 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat) were used to conduct in-vivo experiments using mouse models. Intravenous and oral administration of ICA-1S resulted in the reduction of tumor growth by approximately 30% in athymic nude mice for U-87 xenografts. Taken together, these results suggest that not only do aPKCs play a central role in GB progression, invasiveness, and cell survival, but that effective therapeutics can be developed to specifically target oncogenic aPKCs. Citation Format: Luke Lajmi, Wishrawana S. Ratnayake, Khandker M. Khalid, Sloan Breedy, Aaron Todman, Tracess Smalley, Christopher A. Apostolatos, Robert Hill, Mildred Acevedo-Duncan. PKC-ι/ζ signaling is crucial for apoptosis/pyroptosis inhibition and invasiveness of glioblastoma cells through upregulation of β-catenin, PDK1/Akt1 and Smad cascades via 14-3-3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4382.
Abstract 4859: Mental health of early-onset and late-onset cancer survivors
Authors: Jayden H. Lee, Jaejin An
Journal: Cancer Research (2024)

Abstract Background: Psychiatric disorders such as anxiety and depression are shown to be common when diagnosed with early-onset cancer, often defined as cancers diagnosed in adults &amp;lt;50 years of age. We hypothesize that the mental health of early-onset cancer survivors is negatively affected compared to late-onset cancer survivors. Methods: We identified cancer survivors in the Medical Expenditure Panel Survey 2021 Full Year Consolidated Data File. We categorized cancer survivors as early-onset (≤ 50 years of age) and late-onset (&amp;gt; 50 years of age). We examined the proportion of mood and anxiety disorders, and the proportion of antidepressant and antianxiety medication use among the early and late-onset cancer survivors. We conducted chi-square tests and multivariable logistic regression models by adjusting for sex and race. Results: We identified 291 early-onset cancer survivors (mean age 41 years, 71% female) and 2556 late-onset cancer survivors (mean age 71 years, 56% female). Among the early-onset cancer survivors, 18% had mood disorders (17% took antidepressants) and 20% had anxiety disorders (6% took antianxiety medication). In comparison, 12% late-onset cancer survivors had mood disorders (21% took antidepressants) and 13% had anxiety disorders (8% took antianxiety medication). Early-onset cancer survivors were more likely to develop mood (Adjusted Odds Ratio (aOR)=1.45; 95% CI=1.06 - 1.99) and anxiety (aOR=1.42; 95% CI=1.05 - 1.92) disorders compared to late-onset cancer survivors. However, there were no differences in receiving antidepressants (aOR=0.79; 95% CI=0.57 - 1.09) or antianxiety (aOR=0.69; 95% CI=0.41 - 1.16) medication between early and late-onset cancer survivors when adjusting for sex and race. Conclusion: Early-onset cancer survivors had an elevated risk of acquiring psychiatric disorders such as mood and anxiety disorders than late-onset cancer survivors, but treatment was suboptimal. Clinician and patient awareness can help narrow the gaps of treatment for early-onset cancer survivors. Table 3. Odds Ratio for early-onset vs. late-onset cancer survivors (*Sex and Race adjusted) Variables Crude Odds Ratio Adjusted Odds Ratio * Mood Disorders 1.48 (1.09 - 2.00) 1.45 (1.06 - 1.99) Anxiety Disorder 1.52 (1.13 - 2.03) 1.42 (1.05 - 1.92) Antidepressants 0.80 (0.59 - 1.10) 0.79 (0.57 - 1.09) Antianxiety 0.70 (0.42 - 1.17) 0.69 (0.41 - 1.16) Citation Format: Jayden H. Lee, Jaejin An. Mental health of early-onset and late-onset cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4859.
Abstract 5687: Downregulation of DAX-1 expression by miRNA overexpression as a mechanism to potentiate breast cancer
Authors: Nicholas C. DeVito, Christina Tzagarakis-Foster
Journal: Cancer Research (2024)

Abstract The orphan nuclear receptor DAX-1 (Dosage Sensitive Sex Reversal, Adrenal Hypoplasia Congenita, critical region on the X chromosome, gene 1) plays a key role in sex determination and the synthesis of steroid hormones. In addition to these canonical examples, DAX-1 has been shown to play a contradictory role in cancer development. While DAX-1 is overexpressed in some types of cancer, it is completely absent or downregulated in several other cancers such as prostate and breast. One of the explanations for the paradoxical role of DAX-1 in cancer development could be microRNAs (miRNAs). Recent research has demonstrated that the dysregulated expression of these short non-coding RNAs increases the proliferative and anti-apoptotic capabilities of cancer cells. After broadly surveying over 180 miRNAs historically upregulated in MCF7 cells, we compared the activity of DAX-1 in MCF7 breast cancer cells and MCF10a normal breast epithelial cells with the presence of specific miRNA inhibitors. Our primary hypothesis remains that multiple miRNAs negatively regulate the expression of DAX-1 in human breast cancer cells and are not overexpressed in normal breast cells, providing another mechanism of lifting the repression of DAX-1 expression. Quantitative PCR and western blot analysis was performed indicating that inhibiting miRNAs 29c, 199a, and 424 significantly upregulate DAX-1 expression in MCF10a cells. We examined the invasive and metastatic properties of MCF7 cells following inhibition of these specific miRNAs. This research will allow clinicians to screen for additional miRNAs that could be elevated in breast cancer patients substantially increasing the number of people diagnosed with breast cancer early on. In addition, elucidating the pathways of how more and more miRNAs influence downstream targets will offer drug designers novel targets to improve treatment for breast cancer and other cancer patients. Citation Format: Nicholas C. DeVito, Christina Tzagarakis-Foster. Downregulation of DAX-1 expression by miRNA overexpression as a mechanism to potentiate breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5687.
Abstract 7194: Targeting AXL and MCL-1 to eradicate lazertinib tolerance in EGFR-mutated NSCLC cells
Authors: Tadaaki Yamada, Yohei Matsui, Koichi Takayama
Journal: Cancer Research (2024)

Abstract Lazertinib, a novel third-generation EGFR-tyrosine kinase inhibitor, has shown marked efficacy in patients with EGFR-mutant lung cancer. However, after various periods of therapeutic intervention, most patients eventually acquire resistance to lazertinib. A potential therapeutic approach to address this clinical issue is to overcome the initial drug resistance mechanism. To determine the underlying adaptive lazertinib resistance mechanisms, we evaluated signal transduction, cell apoptosis, and drug sensitivity in mutant EGFR-expressing non-small cell lung cancer (NSCLC) cells treated with lazertinib. The siRNA screening assay demonstrated that AXL knockdown significantly inhibited cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long-term culture with a combination of lazertinib and AXL inhibitors eventually led to the proliferation of residual cells and increased MCL-1 expression, which was mediated by the nuclear translocation of the transcription factor YAP. Cell-based assays showed that triple therapy with an MCL-1 or YAP inhibitor, in combination with EGFR-TKI lazertinib, an AXL inhibitor, significantly reduced cell viability and increased apoptosis. These results demonstrate that AXL and YAP/MCL-1 signals contribute to the adaptive lazertinib resistance in EGFR-mutant NSCLC cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be highly effective in eliminating lazertinib-resistant cells. Citation Format: Tadaaki Yamada, Yohei Matsui, Koichi Takayama. Targeting AXL and MCL-1 to eradicate lazertinib tolerance in EGFR-mutated NSCLC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7194.
Abstract 5586: Hijacking mutant E3 ligase for targeted protein degradation: Discovery of cancer-specific PROTACs for the treatment of FBXW7 R465C driven cancers
Authors: Hailong Zhang
Journal: Cancer Research (2024)

Abstract Many cancers carry LOF mutations of tumor suppressor genes and drug discovery against these cancers are challenging. Fbxw7 is a major tumor suppressor E3 ligase and is frequently mutated (LOF) in cancer. Fbxw7 R465C mutation correlates with worse survival and resistance to both chemo- and targeted therapies. Blueray have discovered Fbxw7 R465C-selective ligands and developed PROTAC molecules selectively targeting cancers carrying Fbxw7 R465C mutation. The Fbxw7 R465C-based PROTACs show superior degradation activity for several target proteins and inhibit proliferation of cancer cells carrying Fbxw7 R465C mutations. These PROTACs show tumor growth inhibition in Fbxw7 R465C mutant cell derived xenograft models with clear PK/PD correlations. Development of bi-functional molecules such as PROTACs bring new options to target cancers with LOF mutations. Citation Format: Hailong Zhang. Hijacking mutant E3 ligase for targeted protein degradation: Discovery of cancer-specific PROTACs for the treatment of FBXW7 R465C driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5586.
Abstract 7080: Regulation of caveolin-1 by RAS/RAF oncogenic signaling in cancer cells
Authors: Veronica Castro Aceituno, Tiantian Cui, Haihua Feng, Linlin Yang, Sindhu Nair, Terence M. Williams
Journal: Cancer Research (2024)

Abstract Background and Purpose: Caveolin-1 (Cav-1), a scaffolding protein implicated in cellular signaling and membrane dynamics, undergoes intricate regulation at multiple levels. Recent evidence has suggested a potential association between oncogenic mutations and alterations in Cav-1 expression. Our study aimed to comprehensively explore how RAS/RAF mutations influence Cav-1 expression in cancer cells, as well as the underlying molecular mechanisms, using tetracycline (tet)-inducible cell lines and cancer cell lines harboring endogenous BRAF or KRAS mutations. Experimental Design: We assessed the regulation of Cav-1 expression using tet-inducible cell lines with BRAFV600E, KRASG12D, or KRASG12C mutations. We measured the half-life of Cav-1 at protein levels by using cycloheximide. We monitored Cav-1 localization and degradation dynamics by SNAP-based pulse-chase assay. Additionally, we performed protein and gene expression analyses by immunoblotting and qRT-PCR, luciferase reporter assay, and immunofluorescence to dissect the impact of BRAF and KRAS mutations on Cav-1 regulation at various stages of its life cycle. Results: We found a significant downregulation of Cav-1 at both mRNA and protein levels upon induction of BRAF or KRAS mutations. The use of KRASG12C, BRAFV600E, ERK, and/or MEK inhibitors in tet-inducible cell lines rescued the effects observed upon induction. The rescue effects have also been observed in H23, MiaPaCa-2 and 8505-C cancer cell lines bearing either BRAF or KRAS mutations. Notably, BRAFV600E exhibited a more pronounced reduction in Cav-1 expression than other mutations. We observed shortened half-life of Cav-1 at protein levels after induction of RAS/RAF mutations by using cycloheximide, and SNAP-based pulse-chase. These mutations accelerated lysosomal-mediated degradation of Cav-1 as determined by immunoblotting and immunofluorescence, which was reversed by lysosomal inhibitors. Conclusions: Our study establishes a novel regulatory paradigm wherein RAS/RAF mutations exert a multi-faceted influence on Cav-1 dynamics in cancer cells. The transcriptional and translational downregulation, coupled with accelerated lysosomal degradation, collectively contributes to the decreased half-life of Cav-1 following the induction of BRAF or KRAS mutations. These findings provide insights into the intricate molecular mechanisms underpinning the dysregulation of Cav-1 in the context of RAS/RAF mutations, offering potential avenues for therapeutic interventions. Citation Format: Veronica Castro Aceituno, Tiantian Cui, Haihua Feng, Linlin Yang, Sindhu Nair, Terence M. Williams. Regulation of caveolin-1 by RAS/RAF oncogenic signaling in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7080.
Abstract 5670: CRISPR-Mediated knockout of Ceruloplasmin (CP) and UCHL1 reveals angiogenic role in renal cell carcinoma (RCC) cell survival and proliferation
Authors: Wagma Caravan, Yige Wu, Preet Lal, Kazu Sato, Yize Li, Nataly Naser Al Deen, Siqi Chen, Ateih Abedin, Feng Chen, Li Ding
Journal: Cancer Research (2024)

Abstract Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma, accounting for approximately 70% of all cases. Therapeutic treatment for metastatic ccRCC involve tyrosine kinase inhibitors or mTOR inhibiters. While these drugs extend patient survival, it also introduces a range of adverse side effects. Utilizing snRNA sequencing, snATACseq, and spatial transcriptomics, two potential ccRCC tumor specific markers have been identified: ceruloplasmin (CP) and UCHL1. These markers are notably overexpressed in a majority of ccRCC tumor cells and elevated CP levels have been correlated with reduced patient survival. To investigate the roles of CP and UCHL1 in ccRCC, CRISPR-based knockout experiments were conducted on two RCC cell lines, namely RCC4-VHL- and Caki-1. Through cell line characterization assays, we find that the absence of CP and UCHL1 impairs the cells' capabilities to migrate, proliferate, and adhere. Additionally, Cell-Derived Xenografts (CDX) of the knockout cell lines in nude mice revealed that cells lacking UCHL1 exhibited slower tumor growth compared to their parental lines. Bulk RNA sequencing further suggested a potential interrelationship between CP and UCHL1, as CP knockout cells showed increased UCHL1 expression relative to the parental line. These findings open new avenues for potential therapeutic strategies and biomarkers in the treatment and screening of ccRCC and further elevates our understandings of the roles of CP and UCHL1 in RCC tumor progression. Citation Format: Wagma Caravan, Yige Wu, Preet Lal, Kazu Sato, Yize Li, Nataly Naser Al Deen, Siqi Chen, Ateih Abedin, Feng Chen, Li Ding. CRISPR-Mediated knockout of Ceruloplasmin (CP) and UCHL1 reveals angiogenic role in renal cell carcinoma (RCC) cell survival and proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5670.
Abstract 4399: HMGA1 is an epigenetic regulator and plays a critical role in melanoma recurrence
Authors: Haiwei Mou, Kristen DeRosa, Veronika Yakovishina, Yeqing Chen, Abdiel Mandella Reynolds, Min Xiao, Monzy Thomas, Meenhard Herlyn
Journal: Cancer Research (2024)

Abstract Among various genetic mutation in melanoma, BRAFV600E is one of the key drivers of melanoma initiation and progression and has become the frontline target in clinical trials. Although BRAF/MEK inhibitors show very promising therapeutic outcomes, recurrence or relapse is still a major challenge and its underlying mechanisms are still poorly understood. We hypothesized that survival of recurrent tumors is BRAF independent and relies on epigenetic reprogramming. To test our hypothesis, we used either pharmacological inhibition of BRAF/MEK or CRISPR/Cas9 mediated knockout of BRAF to create cell/tumor models of BRAF-independent survival. Cut&amp;Run sequencing was then used to identify epigenetic alterations regulated by H3K4me3 or H3K27Ac in a genome scale and capture the landscape of epigenetic alterations of BRAF-independent cell survival. Combining regular bulk RNAseq, we narrowed down our top candidates and focused on one of the functionally validated candidates, HMGA1. Interestingly, CRISPR/Cas9 mediated HMGA1 knockout cells show significantly slower growth in both in vitro colony formation assays and in vivo xenografts assay in BRAF/MEK resistant Patient-Derived-Xenograft (PDX) tumor models resembling melanoma recurrence. Furthermore, we selected CRISPR/Cas9 single knockout cells of HMGA1, which is a pure genetic depletion model, and confirmed the phenotype of impaired tumor growth of HMGA1 knockout cells. We then performed RNAseq and ChIPseq, and identified downstream targets of HMGA1 and elucidated mechanisms by which HMGA1 reprograms epigenetics of recurrence. Utilizing the single knockout cell, we re-introduced HMGA1 in the pure knockout cells, and anticipated that restoration of HMGA1 in pure HMGA1 knockout cells rescues impaired tumor growth and confer cells resistance to BRAF/MEK inhibition. Finally, we subcutaneously injected the HMGA1 single knockout cells into humanized mice and tested whether epigenetic alterations perturb the immune microenvironment and sensitize cells to immunotherapy. In conclusion, this study sheds new lights on how melanoma cells reprogram the epigenome to develop mechanisms of recurrence. Identification of HMGA1 and its upstream or downstream targets provides potential druggable targets of overcoming relapse after BRAF/MEK inhibitor therapy. Citation Format: Haiwei Mou, Kristen DeRosa, Veronika Yakovishina, Yeqing Chen, Abdiel Mandella Reynolds, Min Xiao, Monzy Thomas, Meenhard Herlyn. HMGA1 is an epigenetic regulator and plays a critical role in melanoma recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4399.