tbuckley/cabot-search huggingface dataset:
Abstract P36: BIOLOGY IN ACUTE LYMPHOBLASTIC LEUKEMIA FROM DIAGNOSIS TO FOLLOW-UP: A STUDY OF 48CASES
Authors: Abou A Koundio, Moussa Ndour, Mame Ndella Diouf, Fatou Binetou Akonde, Awa Oumar Toure, Martine Raphael
Journal: Blood Cancer Discovery (2024)

Abstract OBJECTIVE: ALL is the most common cancer in children and the most common cause of cancer death before the age of 20. In low- and middle-income countries, ALL is associated with poor outcomes. Many constraints are at the root of management failures. Therefore, in view of the progressive improvements in the efficacy of chemotherapeutic regimens, we deemed it necessary to conduct this study, the objective of which is to evaluate the role of biology in the management of children with ALL in the Oncopediatric Unit of Dakar. METHODS: This is a prospective analytical study that started on November 15th, 2021 at the UOP in collaboration with the hematology and immunology laboratories. All newly diagnosed patients with ALL based-on cytology and/or immunophenotyping, treated according to the ALL-GFAOP protocol and registered in the REDcap database are included. RESULTS: From November, 15th 2021 to July, 31th 2023, 48 patients were diagnosed with de novo ALL. With an average age of 7.8 years, female represented the main group (52,08%). According to immunophenotyping, the B profile was found in 25.0 % and the T profile in 22.9 %. The ALL T group was older (9.2 vs 4.4 years) and have had higher platelet counts (122272.7 vs 46916.7) at diagnosis than the ALL B group. This latter had higher hemoglobin (7.4 vs 6.8), white blood cell (127296.2 vs 56511.2) and blast counts at diagnosis in peripheral blood (69.4% vs 55.1%) and also in bone marrow (84.2% vs 72.5%) and higher rate of residual blast counts at Day8 after induction (9198.4 vs 1301.4). Regarding corticosensitivity at D8 of induction, no difference was found according to the number of blasts, the hemoglobinlevel and the immunological profile at diagnosis. However, patients with hyperleukocytic ALL with a relatively higher platelet count were more sensitive to corticosteroid therapy. CONCLUSIONS: Understanding the biology of acute ALL is of major interest in the effectiveness of therapeutic approaches to this type of hematology malignancies. Citation Format: Abou A Koundio, Moussa Ndour, Mame Ndella Diouf, Fatou Binetou Akonde, Awa Oumar Toure, Martine Raphael. BIOLOGY IN ACUTE LYMPHOBLASTIC LEUKEMIA FROM DIAGNOSIS TO FOLLOW-UP: A STUDY OF 48CASES [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P36.
Abstract P31: Graph-Based Deep Learning for Predicting Synergy in Multi-Drug Treatments for Leukemia
Authors: Archishma Marrapu
Journal: Blood Cancer Discovery (2024)

Abstract Leukemia, a cancer impacting blood-forming tissues such as bone marrow and the lymphatic system, presents in various forms, affecting children and adults differently. The therapeutic approach is complex and depends on the specific leukemia type. Effective management is crucial as it disrupts normal blood cell production, increasing infection susceptibility. Treatments like chemotherapy can further weaken immunity. Thus, a patient’s healthcare plan should focus on comfort, reducing chemotherapy side effects, protecting veins, addressing complications, and offering educational and emotional support. One of the greatest challenges we face in cancer research and treatment is the ability of cancer to adapt, evolve, and become drug-resistant. We expect that the future of cancer treatment will be in combining therapies to overcome resistance – but we need to get much better at predicting which drug combinations will work best for individual patients. Recent studies showed that a combination of two drugs keeps patients with chronic lymphocytic leukemia disease-free and alive longer than the current standard of care, according to the Stanford University School of Medicine and multiple other institutions. This article proposes studies on the combined use of drugs for treating leukemia. Employing a mix of medicines might decrease the chances of tumor resistance. Starting multiple drugs concurrently allows for immediate application during disease onset, avoiding delays. Initial chemotherapy uses a drug combination to eliminate maximum leukemia cells and restore normal blood counts. Afterward, intensification chemotherapy targets any residual, undetectable leukemia cells in the blood or bone marrow. To recommend a drug combination to treat/manage Leukemia, we have employed a Graph Neural Network to pass information between these trending drugs and genes that act as potential targets for Leukemia. Citation Format: Archishma Marrapu. Graph-Based Deep Learning for Predicting Synergy in Multi-Drug Treatments for Leukemia [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P31.
Abstract P28: Immunoproteasome inhibitors for the treatment of ALL
Authors: Alexei F Kisselev
Journal: Blood Cancer Discovery (2024)

Abstract The t(4;11)(q21;q23) chromosomal translocation that creates the MLL-AF4 fusion protein, confers a poor prognosis in infant acute lymphoblastic leukemia (ALL). This translocation also sensitizes cells to proteasome inhibitors bortezomib and carfilzomib, which are approved by the FDA for the treatment of multiple myeloma. Clinical activity of bortezomib in combination with standard chemotherapy has been documented in several clinical trials of ALL patients, and a case of a single-agent activity against relapsed leukemia driven by the MLL-AF4 translocation has been described. However, toxicities of bortezomib and carfilzomib linmit their use to treat to pediatric patients. We found that the overwhelming majority of proteasomes in this subtype of ALL are lymphoid tissue specific immunoproteasomes. Cells with MLL-AF4 translocations were sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitors ONX-0914 and M3258. Furthermore, both compounds dramatically delayed growth of orthotopic xenograft tumors in mice, and improved responce to induction chemotherapy. Thus, immunoproteasomes are therapeutic targets in ALL and replacing bortezomib and carfilzomib with immunoproteasome inhibitors in ALL should reduce toxicities associated with inhibition of the proteasomes in non-lymphoid tissues. Citation Format: Alexei F Kisselev. Immunoproteasome inhibitors for the treatment of ALL [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P28.
MBNL1 Regulates Programmed Postnatal Switching Between Regenerative and Differentiated Cardiac States
Authors: Logan R.J. Bailey, Darrian Bugg, Isabella M. Reichardt, C. Dessirée Ortaç, Abigail Nagle, Jagadambika Gunaje, Amy Martinson, Richard Johnson, Michael J. MacCoss, Tomoya Sakamoto, Daniel P. Kelly, Michael Regnier, Jennifer Davis
Journal: Circulation (2024)

BACKGROUND: Discovering determinants of cardiomyocyte maturity is critical for deeply understanding the maintenance of differentiated states and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Forced dedifferentiation paired with oncogene expression is sufficient to drive cardiac regeneration, but elucidation of endogenous developmental regulators of the switch between regenerative and mature cardiomyocyte cell states is necessary for optimal design of regenerative approaches for heart disease. MBNL1 (muscleblind-like 1) regulates fibroblast, thymocyte, and erythroid differentiation and proliferation. Hence, we examined whether MBNL1 promotes and maintains mature cardiomyocyte states while antagonizing cardiomyocyte proliferation. METHODS: MBNL1 gain- and loss-of-function mouse models were studied at several developmental time points and in surgical models of heart regeneration. Multi-omics approaches were combined with biochemical, histological, and in vitro assays to determine the mechanisms through which MBNL1 exerts its effects. RESULTS: MBNL1 is coexpressed with a maturation-association genetic program in the heart and is regulated by the MEIS1/calcineurin signaling axis. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, whereas loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of estrogen-related receptor signaling was essential for maintaining cardiomyocyte maturity in adult myocytes. In accordance with these data, modulating MBNL1 dose tuned the temporal window of neonatal cardiac regeneration, where increased MBNL1 expression arrested myocyte proliferation and regeneration and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. However, MBNL1 deficiency was insufficient to promote regeneration in the adult heart because of cell cycle checkpoint activation. CONCLUSIONS: Here, MBNL1 was identified as an essential regulator of cardiomyocyte differentiated states, their developmental switch from hyperplastic to hypertrophic growth, and their regenerative potential through controlling an entire maturation program by stabilizing adult myocyte mRNAs during postnatal development and throughout adulthood. Targeting loss of cardiomyocyte maturity and downregulation of cell cycle inhibitors through MBNL1 deletion was not sufficient to promote adult regeneration.
Abstract IA013: Unique metabolic changes in Lynch syndrome-associated endometrial cancer
Authors: Melinda S. Yates
Journal: Clinical Cancer Research (2024)

Abstract Lynch syndrome-associated endometrial cancers (ECs) are defined by germline mutations in DNA mismatch repair genes, including MSH2, MSH6, PMS2, and MLH1. Lynch syndrome (LS) tumors have received increased attention in the therapeutic context as these tumors are microsatellite instable and often reflect increased immune cell infiltration and enhanced response to immunotherapy. However, relatively little attention has been paid to pathogenesis of LS ECs. Women with LS represent an at-risk population who could benefit from cancer interception strategies due to a 60% cumulative lifetime risk of developing EC. We developed a mouse model of MSH2 loss targeted to the uterus to evaluate EC pathogenesis, with the goal of elucidating mechanisms that alter disease penetrance for women with hereditary risk for EC development. Our Progesterone Receptor-Cre Msh2f lox/flox mice (abbreviated Msh2KO) develop ECs that closely mimic human EC. Whole transcriptome profiling of Msh2KO EC and Msh2KO normal endometrium compared to wild-type endometrium identified “Mitochondrial dysfunction” as a significantly altered pathway in Msh2 deficiency, prompting our in-depth evaluation of mitochondrial alterations in Msh2KO mice, MSH2-deficient cell lines, and LS-associated EC patient specimens. We will discuss the impact of MSH2 deficiency across multiple measures of mitochondrial content, integrity, function, and metabolomic analyses in ECs using preclinical models and human tissue studies. Overall, our studies reveal that MSH2-deficient EC is characterized by mitochondrial DNA damage, mitochondrial content reduction, and decreased mitochondrial function. In addition, decreased mitochondrial respiration for energy production facilitates metabolic reprogramming toward glycolysis. We are conducting further studies to define mechanisms underlying mitochondrial defects due to MSH2 loss and opportunities for intervention. Mitochondrial and metabolic aberrations could serve as novel biomarkers for EC development and targets for cancer prevention in women with LS. Citation Format: Melinda S. Yates. Unique metabolic changes in Lynch syndrome-associated endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA013.
Highlighted research articles
Journal: Blood Cancer Discovery (2024)

In This Issue| March 01 2024 Highlighted research articles Author & Article Information Online ISSN: 2643-3249 Print ISSN: 2643-3230 ©2024 American Association for Cancer Research2024American Association for Cancer Research Blood Cancer Discov (2024) 5 (2): 80. https://doi.org/10.1158/2643-3230.BCD-5-2-ITI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record March 1 2024 Citation Highlighted research articles. Blood Cancer Discov 1 March 2024; 5 (2): 80. https://doi.org/10.1158/2643-3230.BCD-5-2-ITI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Preclinical strategies to identify novel drug combinations often prioritize synergistic drug combinations: those which perform better than would be expected based on the monotherapy activities. In this issue, Mason-Osann et al. use live cell imaging to demonstrate that synergistic drug combinations increase the likelihood of resistance developing and the fitness benefit conferred by resistance, because resisting one drug disrupts the synergy. This experimental data is supported by computational modeling, and analysis of patient-derived tumor xenografts and clinical data. These findings suggest a reevaluation of preclinical screening, emphasizing response durability and cautioning against prioritizing combinations of individually weak drugs based on short-term synergy. See article, p. 95. Clinical responses to CD19-targeting CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (rrLBCL), while encouraging, remain heterogeneous and are often accompanied by serious immunotoxicities. In this work, Faramand, Lee, Jain et al. offer a simple risk stratification system identifying risks of high-grade immune-related... You do not currently have access to this content.
Abstract IA003: The future of endometrial cancer research: possibility and purpose
Authors: Kemi Doll
Journal: Clinical Cancer Research (2024)

Abstract This talk will review the growing problem of endometrial cancer in the United States, discussing the state of the science, ongoing investigations, and promises of future progress along the entire endometrial cancer care continuum. An emphasis on health equity, workforce diversity, and patient-centeredness will be included. Citation Format: Kemi Doll. The future of endometrial cancer research: possibility and purpose [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA003.
Persisting cancer cells are different from bacterial persisters
Authors: Morgane Decollogny, Sven Rottenberg
Journal: Trends in cancer (2024)

The persistence of drug-sensitive tumors poses a significant challenge in cancer treatment. The concept of bacterial persisters, which are a subpopulation of bacteria that survive lethal antibiotic doses, is frequently used to compare to residual disease in cancer. Here, we explore drug tolerance of cancer cells and bacteria. We highlight the fact that bacteria, in contrast to cancer cells, have been selected for survival at the population level and may therefore possess contingency mechanisms that cancer cells lack. The precise mechanisms of drug-tolerant cancer cells and bacterial persisters are still being investigated. Undoubtedly, by understanding common features as well as differences, we, in the cancer field, can learn from microbiology to find strategies to eradicate persisting cancer cells.
BLUPmrMLM: A Fast mrMLM Algorithm in Genome-wide Association Studies
Authors: Hong-Fu Li, Jing-Tian Wang, Qiong Zhao, Yuan-Ming Zhang
Journal: Genomics Proteomics & Bioinformatics (2024)

Multilocus genome-wide association study has become the state-of-the-art tool for dissecting the genetic architecture of complex and multiomic traits. However, most existing multilocus methods require relatively long computational time when analyzing large datasets. To address this issue, in this study, we proposed a fast mrMLM method, namely, best linear unbiased prediction multilocus random-SNP-effect mixed linear model (BLUPmrMLM). First, genome-wide single-marker scanning in mrMLM was replaced by vectorized Wald tests based on the best linear unbiased prediction (BLUP) values of marker effects and their variances in BLUPmrMLM. Then, adaptive best subset selection (ABESS) was used to identify potentially associated markers on each chromosome to reduce computational time when estimating marker effects via empirical Bayes. Finally, shared memory and parallel computing schemes were used to reduce the computational time. In simulation studies, BLUPmrMLM outperformed GEMMA, EMMAX, mrMLM, and FarmCPU as well as the control method (BLUPmrMLM with ABESS removed), in terms of computational time, power, accuracy for estimating quantitative trait nucleotide positions and effects, false positive rate, false discovery rate, false negative rate, and F1 score. In the reanalysis of two large rice datasets, BLUPmrMLM significantly reduced the computational time and identified more previously reported genes, compared with the aforementioned methods. This study provides an excellent multilocus model method for the analysis of large-scale and multiomic datasets. The software mrMLM v5.1 is available at BioCode (https://ngdc.cncb.ac.cn/biocode/tool/BT007388) or GitHub (https://github.com/YuanmingZhang65/mrMLM).
Abstract IA014: Personalized adjuvant treatment in endometrial cancer
Authors: Tjalling Bosse
Journal: Clinical Cancer Research (2024)

Abstract The majority of endometrial cancer patients are cured by surgical removal of the uterus. Adjuvant treatment is recommended for a subset of patients with tumor characteristics associated with increased risk of recurrence. Historically pathologists have played a central role in defining histopathological factors that together make-up a risk profile which directs the type of adjuvant treatment. This traditional approach suffers from interobserver variability and lacks a biological basis. With the advance of molecular pathology, we have been able to define molecularly distinct endometrial cancer subsets which also carry distinct prognostic information and may form a basis for targeted adjuvant treatment. The RAINBO program exploits this concept by running 4 molecular subclass specific clinical trials. During my talk I will go over the past, the present and the future of adjuvant treatment in endometrial cancer with an emphasis on the role of pathology. Citation Format: Tjalling Bosse. Personalized adjuvant treatment in endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA014.
Ongoing measles outbreak, the Federation of Bosnia and Herzegovina, December 2023 to February 2024
Authors: Sanjin Musa, Irma Salimović-Bešić, Jasmina Brkić Džambić, Nijaz Tihić, Anisa Bajramović, Suzana Arapčić, Amela Dedeić-Ljubović, Siniša Skočibušić
Journal: Eurosurveillance (2024)

We report on an ongoing measles outbreak in the Federation of Bosnia and Herzegovina with 141 cases notified between week 52 2023 and week 6 2024. Among those with known vaccination status, 97% were unvaccinated and the most affected group is children under the age of 5 years (n = 87) who were not vaccinated during the pandemic years. Sixty-eight cases were hospitalised, the most common complications were measles-related pneumonia and diarrhoea. The sequenced measles viruses from four cases belonged to genotype D8.
Abstract IA011: Understanding field carcinogenesis in obesity-related endometrial cancer
Authors: Ronald Chandler
Journal: Clinical Cancer Research (2024)

Abstract Over the last decade, endometrial cancer (EC) incidence has increased at an average rate of 0.8% each year. Although cancer death rates decreased during this time, EC showed the greatest increase in cancer death among women. Public awareness of EC remains low, and EC research remains underfunded relative to its societal burden. While most women with EC are post-menopausal, up to 30% of cases occur in pre-menopausal women under 50 years of age, with obesity being a major risk factor. More than half of all EC is associated with obesity. Obesity is also a leading risk factor for benign endometrial hyperplasia, which is considered the precursor lesion to EC. Like other cancers, the causes of EC are multifactorial, with obesity and somatic mutations playing causal roles. By 2030, half of all adult women in the U.S. are expected to be classified as obese. Therefore, EC incidence is expected to increase. If detected early, EC can be cured with surgical hysterectomy, but this solution is not ideal for all women. Intentional weight loss can lower endometrial cancer risk in obese women, but certain barriers prevent obese, at-risk women from losing weight or maintaining healthy lifestyles while living in obesogenic environments. There is a critical need to understand the biological mechanisms underlying EC pathogenesis in at-risk obese women. Although EC is thought to arise from a hyperplastic endometrial epithelium, our previous findings suggest that high-fat diet induced obesity affects other cell types within the endometrial microenvironment, including endometrial stroma and immune cells, in the absence of histopathological change. Common EC somatic mutations can also arise in the absence of histopathological change or occur in cases of benign disease. Our overarching hypothesis is that a normal appearing endometrium may accrue cell-context dependent alterations in response to obesity and somatic mutations across a pre-malignant tissue field that are predictive of malignant transformation. This presentation will highlight our recent work on the combined molecular and phenotypic effects of obesity and common EC driver mutations on the endometrial tissue field. The identification of high-value molecular targets across the endometrial pre-malignant field may inform new early detection and prevention strategies for EC. Citation Format: Ronald Chandler. Understanding field carcinogenesis in obesity-related endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA011.
A Highly Anticipated Selective Therapeutic Agent against CDK2: INX-315
Authors: Lotte P. Watts, Sabrina L. Spencer
Journal: Cancer Discovery (2024)

Summary: In this issue, Dietrich, Trub, and colleagues describe and characterize a novel selective CDK2 inhibitor: INX-315. This agent shows promise in CCNE1-amplified cancers and in CDK4/6 inhibitor–resistant breast cancers. See related article by Dietrich et al., p. 446 (8).