bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-
Aspergillus
activities of olorofim at sub-MIC levels during early-stage growth
Authors: Kühbacher Alexander , Birch Mike , Oliver Jason D. , Gsaller Fabio 
Published: February 2024

ABSTRACT

Olorofim, the first member of the novel class of antifungal drugs, the orotomides, shows promising anti-
Aspergillus
activity and is currently in phase III clinical development. Using high-throughput microscopy, we monitored olorofim’s antifungal potential at sub-minimum inhibitory concentration (MIC) levels with a focus on early-stage growth. Unlike voriconazole, olorofim showed significant growth inhibitory activities against three main pathogenic
Aspergillus
species,
Aspergillus fumigatus
,
Aspergillus flavus
, and
Aspergillus niger
, at concentrations >100,000-fold below its MIC.

IMPORTANCE

Among antifungal compounds in clinical development for systemic disease, the orotomide olorofim is one of only two that target a completely new mechanism of action. Olorofim is highly potent against pathogenic
Aspergillus
species including cryptic species that frequently show increased resistance to current agents. In this study, our primary focus was on evaluating in detail the inhibitory activity of voriconazole and olorofim against different pathogenic
Aspergillus
species employing high-throughput microscopy. Compared to standardized, less-sensitive visual assessment-based methods, microscopy-assisted growth monitoring allowed us to detect sub-MIC drug concentration ranges with significant inhibitory activity at early-stage growth. This revealed that olorofim exerts growth inhibition at concentrations that are several magnitudes below those of voriconazole.
Design differences and variation in results between randomised trials and non-randomised emulations: meta-analysis of RCT-DUPLICATE data
Authors: Heyard Rachel , Held Leonhard , Schneeweiss Sebastian , Wang Shirley V 
Published: February 2024

Objective
To explore how design emulation and population differences relate to variation in results between randomised controlled trials (RCT) and non-randomised real world evidence (RWE) studies, based on the RCT-DUPLICATE initiative (Randomised, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology).

Design
Meta-analysis of RCT-DUPLICATE data.

Data sources
Trials included in RCT-DUPLICATE, a demonstration project that emulated 32 randomised controlled trials using three real world data sources: Optum Clinformatics Data Mart, 2004-19; IBM MarketScan, 2003-17; and subsets of Medicare parts A, B, and D, 2009-17.

Eligibility criteria for selecting studies
Trials where the primary analysis resulted in a hazard ratio; 29 RCT-RWE study pairs from RCT-DUPLICATE.

Results
Differences and variation in effect sizes between the results from randomised controlled trials and real world evidence studies were investigated. Most of the heterogeneity in effect estimates between the RCT-RWE study pairs in this sample could be explained by three emulation differences in the meta-regression model: treatment started in hospital (which does not appear in health insurance claims data), discontinuation of some baseline treatments at randomisation (which would have been an unusual care decision in clinical practice), and delayed onset of drug effects (which would be under-reported in real world clinical practice because of the relatively short persistence of the treatment). Adding the three emulation differences to the meta-regression reduced heterogeneity from 1.9 to almost 1 (absence of heterogeneity).

Conclusions
This analysis suggests that a substantial proportion of the observed variation between results from randomised controlled trials and real world evidence studies can be attributed to differences in design emulation.
Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity
Authors: Ortmann Brian M 
Published: February 2024

Cancer remains one of the most formidable challenges in modern medicine, due to its complex and dynamic nature, which demands innovative therapeutic approaches. One major challenge to cancer treatment is the tumour microenvironment and in particular tumour hypoxia (low oxygen levels), which contributes to tumour progression and immune evasion. At the cellular level, this is primarily governed by hypoxia-inducible factor (HIF). HIF is a transcription factor that orchestrates cellular responses to low oxygen levels, driving angiogenesis, metabolic adaptation and immune regulation. HIF’s dysregulation is frequently observed in various cancer types and correlates with increased aggressiveness, metastasis, resistance to therapy and poor patient prognosis. Consequently, understanding the cellular mechanisms underlying HIF activation and its downstream effects has become crucial to developing targeted cancer therapies for improving cancer patient outcomes and represents a key step towards precision medicine.Recent advancements in drug development have led to the emergence of HIF inhibitors, which aim to disrupt HIF-driven processes in cancer providing therapeutic benefit. Here, we provide a review of the molecular mechanisms through which HIF promotes tumour growth and resistance, emphasising the potential clinical benefits of HIF-targeted therapies. This review will discuss the challenges and opportunities associated with translating HIF inhibition into clinical practice, including ongoing clinical trials and future directions in the development of HIF-based cancer treatments.
Metastatic gastric cancer target lesion complete response with Claudin18.2-CAR T cells
Authors: Botta Gregory P , Chao Joseph , Ma Hong , Hahn Michael , Sierra Gloria , Jia Jie , Hendrix Amanda Y , Nolte Fong Joy V , Ween Audrey , Vu Peter , Miller Aaron , Choi Michael , Heyman Benjamin , Daniels Gregory A , Kaufman Dan , Jamieson Catriona , Li Zonghai , Cohen Ezra 
Published: February 2024

Treatment of hematologic malignancies with patient-derived anti-CD19 chimeric antigen receptor (CAR) T-cells has demonstrated long-term remissions for patients with otherwise treatment-refractory advanced leukemia and lymphoma. Conversely, CAR T-cell treatment of solid tumors, including advanced gastric cancer (GC), has proven more challenging due to on-target off-tumor toxicities, poor tumor T-cell infiltration, inefficient CAR T-cell expansion, immunosuppressive tumor microenvironments, and demanding preconditioning regimens. We report the exceptional results of autologous Claudin18.2-targeted CAR T cells (CT041) in a patient with metastatic GC, who had progressed on four lines of combined systemic chemotherapy and immunotherapy. After two CT041 infusions, the patient had target lesion complete response and sustained an 8-month overall partial response with only minimal ascites. Moreover, tumor-informed circulating tumor DNA (ctDNA) reductions coincided with rapid CAR T-cell expansion and radiologic response. No severe toxicities occurred, and the patient’s quality of life significantly improved. This experience supports targeting Claudin18.2-positive GC with CAR T-cell therapy and helps to validate ctDNA as a biomarker in CAR T-cell therapy.Clinical Insight:Claudin18.2-targeted CAR T cells can safely provide complete objective and ctDNA response in salvage metastatic GC.
Optimizing quality of life: integrating palliative care for patients with hand-foot syndrome in oncology practice
Authors: Vanumu Divya Sai , Kodisharapu Praveen Kumar , Suvvari Praneeth , Rayani Basanth Kumar , Pathi Nikhil , Tewani Rohan , Rajappa Senthil J 
Published: February 2024

Hand-foot syndrome (HFS) emerges as one of the common dermatological side effects associated with anticancer medications such as 5-fluorouracil (5-FU), capecitabine and docetaxel. This condition can be notably debilitating, exerting a predominant impact on the clinical, functional and psychosocial domains of health. With prevalence rates of HFS, ranging from 43% to 71%, there exists an unmet need among palliative care physicians to comprehend this syndrome in addressing physical, psychological dimensions and its integrated management within healthcare. This understanding enables them to adopt diverse approaches aimed at preserving the quality of life for patients, by enhancing the overall healthcare experience. Our primary objective is to underscore the imperative for the high-quality integration of palliative care with respect to HFS in contemporary oncology practices. We aim to achieve this by providing evidence-based insights to enhance patient outcomes.The intent of this study: (1) The article delves into the range of symptoms linked to HFS, and stresses the necessity of a holistic strategy and the difference that a palliative physician can contribute during cancer treatment—in picking up certain intricate aspects of patient care and addressing them. (2) The article also highlights the comprehensive approach through the incorporation of quality-of-life assessments, with the goal of enhancing patient outcomes, overall care experience within an integrated healthcare framework.
Combining Genomic Biomarkers to Guide Immunotherapy in Non–Small Cell Lung Cancer
Authors: van de Haar Joris , Mankor Joanne M. , Hummelink Karlijn , Monkhorst Kim , Smit Egbert F. , Wessels Lodewyk F.A. , Cuppen Edwin , Aerts Joachim G.J.V. , Voest Emile E. 
Published: February 2024

Abstract

Purpose:
The clinical value of STK11, KEAP1, and EGFR alterations for guiding immune checkpoint blockade (ICB) therapy in non–small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this disease.

Experimental Design:
To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 patients with NSCLC treated with programmed death-ligand 1 (PD-L1) blockade monotherapy, including a discovery cohort of 75 patients subjected to whole-genome sequencing (WGS), and an independent validation cohort of 169 patients subjected to tumor-normal large panel sequencing. The specificity of STK11/KEAP1/EGFR alterations for ICB unresponsiveness was assessed in the contexts of a low (&lt;10 muts/Mb) or high (≥10 muts/Mb) tumor mutational burden (TMB).

Results:
In low TMB cases, STK11/KEAP1/EGFR alterations were highly specific biomarkers for ICB resistance, with 0/15 (0.0%) and 1/34 (2.9%) biomarker-positive patients showing treatment benefit in the discovery and validation cohorts, respectively. This contrasted with high TMB cases, where 11/13 (85%) and 15/34 (44%) patients with at least one STK11/KEAP1/EGFR alteration showed durable treatment benefit in the discovery and validation cohorts, respectively. These findings were supported by analyses of progression-free survival and overall survival.

Conclusions:
The unexpected ICB responses in patients carrying resistance biomarkers in STK11, KEAP1, and EGFR were almost exclusively observed in patients with a high TMB. Considering these alterations in context of the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.
Abstract A053: Dynamic regulation of pyruvate carboxylase is required for immune evasion and pulmonary metastasis
Authors: Coleman Mike , Cotul Eylem Kulkoyluoglu , Teegarden Dorothy , Hursting Stephen , Wendt Mike K 
Published: February 2024

Abstract
Metabolic plasticity is an important mediator of tumor cell survival, growth in various microenvironments, and immune evasion. We present a dimorphic role for for the metabolic enzyme pyruvate carboxylase (PC) in pulmonary metastatic versus primary mammary tumors. Specifically, we demonstrate that PC is essential for metastatic outgrowth in the lungs. In contrast, depletion of PC in tumor cells promotes primary tumor growth. This affect was only observed in immune competent animals, leading us to address the hypothesis that repression of PC can suppress anti-tumor immunity. Exploring key differences between the pulmonary and mammary environments we demonstrate that hypoxia potently downregulated PC. Metabolomic analyses demonstrated that in the absence of PC, tumor cells produce more lactate and undergo less oxidative phosphorylation. Inhibition of lactate metabolism was sufficient to restore T cell populations to PC-depleted mammary tumors and drastcially inhibited primary tumor growth. Along these line, forced overexpression of PC decreased lactate production, increased immune inflitation, and prevented initiation of pulmonary metastases. These findings highlight a key contextual role for PC-directed lactate production as a metabolic nexus connecting hypoxia and antitumor immune suppression in primary tumors and intiating pulmonary metastases. However, following immune evasion and initiation of metastasis the return of PC expression is required for propagation of macroscopic pulmonary metastases.
Citation Format: Mike Coleman, Eylem Kulkoyluoglu Cotul, Dorothy Teegarden, Stephen Hursting, Mike K Wendt. Dynamic regulation of pyruvate carboxylase is required for immune evasion and pulmonary metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A053.
Abstract A070: Examining patient-specific responses to PARP inhibitors in a novel, human induced pluripotent stem cell-based model of breast cancer
Authors: Weddle Carly , Burridge Paul 
Published: February 2024

Abstract
Patient-derived human induced pluripotent stem cells (hiPSCs) are a powerful tool for disease modeling because hiPSCs provide a scalable source of cells that retain patient-specific genomic variants. Recently, somatic cell reprogramming has been applied to modeling cancer: cancer cells are reprogrammed into hiPSCs, then re-differentiated into the relevant cancer cell lineage. hiPSCs derived from cancer cells retain tumor- and subclone-specific genomic variants and drug sensitivities, providing a unique tool to deconstruct the contributions of tumor heterogeneity to drug response. While hiPSCs have been shown to model various hematological malignancies, no study to date has examined the potential of hiPSCs to model breast cancer. We demonstrate for the first time that primary human breast cancer cells can be reprogrammed into hiPSCs by transiently overexpressing canonical reprogramming factors. Using an optimized reprogramming methodology, we generated a biobank of &gt;200 hiPSC lines from 10 breast tumor samples, including hormone receptor positive, HER2 positive, and triple negative breast tumors. Breast tumor-derived hiPSCs retain patient-specific oncogenic variants. Additionally, we present a protocol to differentiate hiPSCs into mammary epithelial cells (hiPSC-MECs) and mammary-like organoids for in vitro disease modeling. hiPSC-MECs are proliferative and exhibit a gene expression profile that closely resembles primary MECs. Finally, we demonstrate that this breast tumor model can be used to assess patient-specific responses to PARP inhibitors. We show that hiPSC-MECs derived from BRCA1 and BRCA2 mutant tumors are deficient in homology-directed repair and are more sensitive to PARP inhibitor treatment. This work establishes the foundation of hiPSCs as a novel disease modeling platform for breast cancer and highlights the potential of tumor-derived hiPSCs to predict patient and subclone-specific drug responses.
Citation Format: Carly Weddle, Paul Burridge. Examining patient-specific responses to PARP inhibitors in a novel, human induced pluripotent stem cell-based model of breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A070.
Abstract A074: Targeting dormant disseminated tumor cells and their permissive niche by pro-resolving mediators derived from resolution-phase macrophages
Authors: Gilon Odelya , Weidenfeld Keren , Samara Hadell , Feuermann Yonatan , Schif-Zuck Sagie , Butenko Sergei , Sabo Edmond , Ariel Amiram , Barkan Dalit 
Published: February 2024

Abstract
Metastatic breast cancer can recur years after primary tumor resection and adjuvant therapy and appears to arise from quiescent disseminated tumor cells (QDTC) that persist at distant sites and resist conventional therapies. To date there are no treatments to target QDTCs. Previously, the fibrotic-like microenvironment enriched with Type I collagen (Col-I) was shown to be required for the switch of QDTC to metastatic outgrowth in lungs of mice. Here, we examined whether soluble mediators secreted by ex-vivo generated pro-resolving CD11blow macrophages (CM-Mres) will reinstate resolution of inflammation thus inhibiting the establishment of the fibrotic-like-niche and in turn prevent the emergence of QDTC to metastatic outgrowth. Our findings indicate that CM-Mres promoted immune silencing of alveolar macrophages at the metastatic site where dormant DTCs reside. Immune silencing is one of the hallmarks of resolution of inflammation. Furthermore, CM-Mres inhibited the establishment of a fibrotic-like niche resulting in the inhibition of the metastatic outgrowth in vitro and in vivo. This was due to inhibition of fibroblasts differentiation to myofibroblasts independent of TGFbeta1 canonical signaling and abolishment of Col-I expression. Furthermore, CM-Mres deactivated myofibroblasts as part of the resolution process by inducing an increase in reactive oxygen species (ROS) via activation of NADPH oxidase. This in turn induced DNA damage leading to Go/G1 arrest and intrinsic apoptosis. Similarly, apoptosis mediated by oxidative stress was induced by CM-Mres in dormant and outbreaking QDTCs. Taken together our results demonstrate for the first time that by reinstating resolution of inflammation via physiological mediators, secreted by pro-resolving macrophages, can prevent metastatic outgrowth of QDTCs at their permissive site. Since conventional therapies fail to eradicate dormant DTCs and their transition to clinical metastasis, our findings hold great promise in the quest to identify novel strategies to prevent or treat recurrent metastatic disease.
Citation Format: Odelya Gilon, Keren Weidenfeld, Hadell Samara, Yonatan Feuermann, Sagie Schif-Zuck, Sergei Butenko, Edmond Sabo, Amiram Ariel, Dalit Barkan. Targeting dormant disseminated tumor cells and their permissive niche by pro-resolving mediators derived from resolution-phase macrophages [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A074.
Abstract A090: Gender Disparities in the National Institutes of Health Funding for Breast Oncology
Authors: Ukrani Janta , Sohail Aruba , Khan Sarah , Zahid Ibrahim , Farooq Muhammad Zain , Jaglal Michael Vishal 
Published: February 2024

Abstract
Introduction As a matter of course, there has been an under-representation of women in academic medicine, resulting in discriminatory distribution of research grants. This study examines the trend of funding allocation of R01 grants in Breast oncology by the National Institutes of Health with specific focus on the distribution of funding between gender. Methods The data were retrieved from the NIH RePORTER (Research Portfolio Online Reporting Tools Expenditure) using breast oncology-related search terms from 2018-2021. The gender was categorized using Genderize. The number of citations, publications, H-index, and seniority were obtained from Scopus and Web of Science in December 2022. Consumer Price Index was used to adjust funding amount to 2021 equivalent U.S. dollars. Linear regression was used for analysis. Results A total of 885 NIH-funded R01 grants amounting to $444.6 million were awarded for breast oncology research. Women (n=390; 44.1% [95% CI: 40.8%-47.3%]) received relatively fewer grants than men (n=495; 55.9% [95% CI: 52.7%-59.2%]). From 2018-2021, there was a significant increase in the number of grants awarded among both men (90 to 155, p&lt;0.01) and women (71 to 115, p=0.036). Similarly, there was a significant increase in the grant amount (in millions) awarded among men (43.4 to 76.5, p&lt;0.01) but not in women (36.7 to 56.1, p=0.11). Of the 212 co-PIs, 133 (62.7% [95% CI: 56.2%-69.2%]) were men and 76 (37.3% [95% CI: 30.8%-43.8%]) were women. There was no significant difference in h-index (48 vs 44, p=0.12), number of publications (158 vs 138, p=0.08), and citations (13272 vs 8092, p=0.06) between the male and female PIs. Funding amount was significantly associated with number of publications (β=0.35, p&lt;0.01), seniority (β=0.25, p&lt;0.01) and institution (p&lt;0.01). Conclusion Our analysis shows continued gender disparity as only 44% of total R01 grants were awarded towards females for breast oncology between the fiscal years 2018 to 2021. Though the proportion of discrepancy is lower as compared to other malignancies. A collaborative effort is still needed to bridge the gap and advance gender equality.
Citation Format: Janta Ukrani, Aruba Sohail, Sarah Khan, Ibrahim Zahid, Muhammad Zain Farooq, Michael Vishal Jaglal. Gender Disparities in the National Institutes of Health Funding for Breast Oncology [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A090.
Abstract B017: Elucidating the role of CPPED1 in triple-negative breast cancer
Authors: Zomorrodinia Talieh 
Published: February 2024

Abstract
Triple-negative breast cancer (TNBC) represents a daunting challenge in clinical oncology due to its aggressive nature and limited treatment options. In light of this unmet need, our research efforts are to gain comprehensive insights into the mechanisms underlying TNBC and explore novel therapeutic strategies. We have identified an enzyme, calcineurin-like phosphoesterase domain-containing protein 1 (CPPED1), that functions as a phosphatase targeting phospho-serine/threonine residues and is amplified in breast cancer. While previous studies on bladder cancer linked CPPED1 to promoting cell death, our preliminary findings in TNBC cell lines, MDA-MB-231 and HS578T, present a contrasting role. Knockdown of CPPED1 in TNBC cell lines leads to reduced cell colony formation and increased apoptosis, indicating its role in promoting cell proliferation in TNBC. Analysis of human patient data from TCGA also shows that expression of CPPED1 is associated with poor survival in both ER+ and ER- breast cancer. These observations hint at CPPED1's potential to exhibit diverse molecular characteristics depending on the cancer type. By thoroughly elucidating the molecular mechanisms and functional role of CPPED1 in breast cancer, our research holds promise in guiding the development of targeted and more effective treatments tailored to address the challenges posed by TNBC.
Citation Format: Talieh Zomorrodinia. Elucidating the role of CPPED1 in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B017.