tbuckley/cabot-search huggingface dataset:
Sonrotoclax overcomes BCL2 G101V mutation–induced venetoclax resistance in preclinical models of hematologic malignancy
Authors: Jiuyang Liu, Shuran Li, Qin Wang, Yingcai Feng, Haimei Xing, Xuefei Yang, Ying Guo, Yunhang Guo, Hanzi Sun, Xiaoxin Liu, Shasha Yang, Zhu Mei, Yutong Zhu, Zhenzhen Cheng, Shuaishuai Chen, Min Xu, Wenjing Zhang, Nanyan Wan, Jia Wang, Yanwen Ma, Shuo Zhang, Xudong Luan, Aiying Xu, Lin Li, Haitao Wang, Xiaolong Yang, Yuan Hong, Hai Xue, Xi Yuan, Nan Hu, Xiaomin Song, Zhiwei Wang, Xuesong Liu, Lai Wang, Ye Liu
Journal: Blood (2024)

Abstract Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation–induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.
Injectable Hydrogels with Integrated Ph Probes and Ultrasound‐Responsive Microcapsules as Smart Wound Dressings for Visual Monitoring and On‐Demand Treatment of Chronic Wounds
Authors: Da Huang, Jiahao Du, Fang Luo, Gang He, Minglang Zou, Yongming Wang, Zhenyu Lin, Decheng Wu, Zuquan Weng
Journal: Advanced Healthcare Materials (2024)

Hydrogel dressings capable of infection monitoring and precise treatment administration show promise for advanced wound care. Existing methods involve embedd ingorganic dyes or flexible electronics into preformed hydrogels, which raise safety issues and adaptability challenges. In this study, an injectable hydrogel based smart wound dressing is developed by integrating food-derived anthocyanidin as a visual pH probe for infection monitoring and poly(L-lactic acid) microcapsules as ultrasound-responsive delivery systems for antibiotics into a poly(ethylene glycol) hydrogel. This straightforwardly prepared hydrogel dressing maintains its favorable properties for wound repair, including porous morphology and excellent biocompatibility. In vitro experiments demonstrated that the hydrogel enabled visual assessment of pH within the range of 5 ∼ 9.Meanwhile, the release of antibiotics could be triggered and controlled by ultrasound. In vivo evaluations using infected wounds and diabetic wounds revealed that the wound dressing effectively detected wound infection by monitoring pH levels and achieved antibacterial effects through ultrasound-triggered drug release. This led to significantly enhanced wound healing, as validated by histological analysis and the measurement of inflammatory cytokine levels. This injectable hydrogel-based smart wound dressing holds great potential for use in clinical settings to inform timely and precise clinical intervention and in community to improve wound care management.
Modulation of multidrug-resistant clone success in Escherichia coli populations: a longitudinal, multi-country, genomic and antibiotic usage cohort study
Authors: Anna K Pöntinen, Rebecca A Gladstone, Henri Pesonen, Maiju Pesonen, François Cléon, Benjamin J Parcell, Teemu Kallonen, Gunnar Skov Simonsen, Nicholas J Croucher, Alan McNally, Julian Parkhill, Pål J Johnsen, Ørjan Samuelsen, Jukka Corander
Journal: The Lancet Microbe (2024)

The effect of antibiotic usage on the success of multidrug-resistant (MDR) clones in a population remains unclear. With this genomics-based molecular epidemiology study, we aimed to investigate the contribution of antibiotic use to Escherichia coli clone success, relative to intra-strain competition for colonisation and infection.
Phase 2 trial of a novel tuberculosis drug launched
Authors: Ed Holt
Journal: The Lancet Microbe (2024)

During the Union World Conference on Lung Health 2023, held in Paris, France, on Nov 15–18, results from preclinical studies and a phase 1 trial of a novel candidate tuberculosis drug were presented. The new compound, named TBAJ-876, belongs to the diarylquinoline class of antibiotics (like bedaquiline).
Genetic mechanisms underlying tumor microenvironment composition and function in diffuse large B-cell lymphoma
Authors: Leandro Cerchietti
Journal: Blood (2024)

Abstract Cells in the tumor microenvironment (TME) of diffuse large B-cell lymphoma (DLBCL) show enormous diversity and plasticity, with functions that can range from tumor inhibitory to tumor supportive. The patient’s age, immune status, and DLBCL treatments are factors that contribute to the shaping of this TME, but evidence suggests that genetic factors, arising principally in lymphoma cells themselves, are among the most important. Here, we review the current understanding of the role of these genetic drivers of DLBCL in establishing and modulating the lymphoma microenvironment. A better comprehension of the relationship between lymphoma genetic factors and TME biology should lead to better therapeutic interventions, especially immunotherapies.
Comprehensive review of CRISPR-based gene editing: mechanisms, challenges, and applications in cancer therapy
Authors: Mohammad Chehelgerdi, Matin Chehelgerdi, Milad Khorramian-Ghahfarokhi, Marjan Shafieizadeh, Esmaeil Mahmoudi, Fatemeh Eskandari, Mohsen Rashidi, Asghar Arshi, Abbas Mokhtari-Farsani
Journal: Molecular Cancer (2024)

Abstract The CRISPR system is a revolutionary genome editing tool that has the potential to revolutionize the field of cancer research and therapy. The ability to precisely target and edit specific genetic mutations that drive the growth and spread of tumors has opened up new possibilities for the development of more effective and personalized cancer treatments. In this review, we will discuss the different CRISPR-based strategies that have been proposed for cancer therapy, including inactivating genes that drive tumor growth, enhancing the immune response to cancer cells, repairing genetic mutations that cause cancer, and delivering cancer-killing molecules directly to tumor cells. We will also summarize the current state of preclinical studies and clinical trials of CRISPR-based cancer therapy, highlighting the most promising results and the challenges that still need to be overcome. Safety and delivery are also important challenges for CRISPR-based cancer therapy to become a viable clinical option. We will discuss the challenges and limitations that need to be overcome, such as off-target effects, safety, and delivery to the tumor site. Finally, we will provide an overview of the current challenges and opportunities in the field of CRISPR-based cancer therapy and discuss future directions for research and development. The CRISPR system has the potential to change the landscape of cancer research, and this review aims to provide an overview of the current state of the field and the challenges that need to be overcome to realize this potential.
Low-Field, Low-Cost, Point-of-Care Magnetic Resonance Imaging
Authors: Anja Samardzija, Kartiga Selvaganesan, Horace Z. Zhang, Heng Sun, Chenhao Sun, Yonghyun Ha, Gigi Galiana, R. Todd Constable
Journal: Annual Review of Biomedical Engineering (2024)

Low-field magnetic resonance imaging (MRI) has recently experienced a renaissance that is largely attributable to the numerous technological advancements made in MRI, including optimized pulse sequences, parallel receive and compressed sensing, improved calibrations and reconstruction algorithms, and the adoption of machine learning for image postprocessing. This new attention on low-field MRI originates from a lack of accessibility to traditional MRI and the need for affordable imaging. Low-field MRI provides a viable option due to its lack of reliance on radio-frequency shielding rooms, expensive liquid helium, and cryogen quench pipes. Moreover, its relatively small size and weight allow for easy and affordable installation in most settings. Rather than replacing conventional MRI, low-field MRI will provide new opportunities for imaging both in developing and developed countries. This article discusses the history of low-field MRI, low-field MRI hardware and software, current devices on the market, advantages and disadvantages, and low-field MRI's global potential.
Genomic and Immunophenotypic Landscape of Acquired Resistance to PD-(L)1 Blockade in Non–Small-Cell Lung Cancer
Authors: Biagio Ricciuti, Giuseppe Lamberti, Sreekar R. Puchala, Navin R. Mahadevan, Jia-Ren Lin, Joao V. Alessi, Alexander Chowdhury, Yvonne Y. Li, Xinan Wang, Liam Spurr, Federica Pecci, Alessandro Di Federico, Deepti Venkatraman, Adriana P. Barrichello, Malini Gandhi, Victor R. Vaz, Andy J. Pangilinan, Danielle Haradon, Elinton Lee, Hersh Gupta, Kathleen L. Pfaff, Emma L. Welsh, Mizuki Nishino, Andrew D. Cherniack, Bruce E. Johnson, Jason L Weirather, Ian D Dryg, Scott J. Rodig, Lynette M. Sholl, Peter Sorger, Sandro Santagata, Renato Umeton, Mark M. Awad
Journal: Journal of Clinical Oncology (2024)

PURPOSE Although immune checkpoint inhibitors (ICI) have extended survival in patients with non–small-cell lung cancer (NSCLC), acquired resistance (AR) to ICI frequently develops after an initial benefit. However, the mechanisms of AR to ICI in NSCLC are largely unknown. METHODS Comprehensive tumor genomic profiling, machine learning–based assessment of tumor-infiltrating lymphocytes, multiplexed immunofluorescence, and/or HLA-I immunohistochemistry (IHC) were performed on matched pre- and post-ICI tumor biopsies from patients with NSCLC treated with ICI at the Dana-Farber Cancer Institute who developed AR to ICI. Two additional cohorts of patients with intervening chemotherapy or targeted therapies between biopsies were included as controls. RESULTS We performed comprehensive genomic profiling and immunophenotypic characterization on samples from 82 patients with NSCLC and matched pre- and post-ICI biopsies and compared findings with a control cohort of patients with non-ICI intervening therapies between biopsies (chemotherapy, N = 32; targeted therapies, N = 89; both, N = 17). Putative resistance mutations were identified in 27.8% of immunotherapy-treated cases and included acquired loss-of-function mutations in STK11, B2M, APC, MTOR, KEAP1, and JAK1/ 2; these acquired alterations were not observed in the control groups. Immunophenotyping of matched pre- and post-ICI samples demonstrated significant decreases in intratumoral lymphocytes, CD3e + and CD8a + T cells, and PD-L1–PD1 engagement, as well as increased distance between tumor cells and CD8 + PD-1 + T cells. There was a significant decrease in HLA class I expression in the immunotherapy cohort at the time of AR compared with the chemotherapy ( P = .005) and the targeted therapy ( P = .01) cohorts. CONCLUSION These findings highlight the genomic and immunophenotypic heterogeneity of ICI resistance in NSCLC, which will need to be considered when developing novel therapeutic strategies aimed at overcoming resistance.
How I use genomics and BTK inhibitors in the treatment of Waldenström macroglobulinemia
Authors: Steven P. Treon, Shayna Sarosiek, Jorge J. Castillo
Journal: Blood (2024)

Abstract Mutations in MYD88 (95%-97%) and CXCR4 (30%-40%) are common in Waldenström macroglobulinemia (WM). TP53 is altered in 20% to 30% of patients with WM, particularly those previously treated. Mutated MYD88 activates hematopoietic cell kinase that drives Bruton tyrosine kinase (BTK) prosurvival signaling. Both nonsense and frameshift CXCR4 mutations occur in WM. Nonsense variants show greater resistance to BTK inhibitors. Covalent BTK inhibitors (cBTKi) produce major responses in 70% to 80% of patients with WM. MYD88 and CXCR4 mutation status can affect time to major response, depth of response, and/or progression-free survival (PFS) in patients with WM treated with cBTKi. The cBTKi zanubrutinib shows greater response activity and/or improved PFS in patients with WM with wild-type MYD88, mutated CXCR4, or altered TP53. Risks for adverse events, including atrial fibrillation, bleeding diathesis, and neutropenia can differ based on which BTKi is used in WM. Intolerance is also common with cBTKi, and dose reduction or switchover to another cBTKi can be considered. For patients with acquired resistance to cBTKis, newer options include pirtobrutinib or venetoclax. Combinations of BTKis with chemoimmunotherapy, CXCR4, and BCL2 antagonists are discussed. Algorithms for positioning BTKis in treatment naïve or previously treated patients with WM, based on genomics, disease characteristics, and comorbidities, are presented.
Improved Cardiomyopathy Risk Prediction Using Global Longitudinal Strain and N-Terminal-Pro-B-Type Natriuretic Peptide in Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy
Authors: Matthew J. Ehrhardt, Qi Liu, Daniel A. Mulrooney, Isaac B. Rhea, Stephanie B. Dixon, John T. Lucas, Yadav Sapkota, Kyla Shelton, Kirsten K. Ness, Deo Kumar Srivastava, Aaron McDonald, Leslie L. Robison, Melissa M. Hudson, Yutaka Yasui, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2024)

To leverage baseline global longitudinal strain (GLS) and N-terminal-pro-B-type natriuretic peptide (NT-proBNP) to identify childhood cancer survivors with a normal left ventricular ejection fraction (LVEF) at highest risk of future treatment-related cardiomyopathy.
Lysine Deacetylation Is a Key Function of the Lysyl Oxidase Family of Proteins in Cancer
Authors: Xingxing Wu, Xue Li, Luwei Wang, Xianxia Bi, Weihong Zhong, Jicheng Yue, Y. Eugene Chin
Journal: Cancer Research (2024)

Abstract Mammalian members of the lysyl oxidase (LOX) family of proteins carry a copper-dependent monoamine oxidase domain exclusively within the C-terminal region, which catalyzes ε-amine oxidation of lysine residues of various proteins. However, recent studies have demonstrated that in LOX-like (LOXL) 2–4 the C-terminal canonical catalytic domain and N-terminal scavenger receptor cysteine-rich (SRCR) repeats domain exhibit lysine deacetylation and deacetylimination catalytic activities. Moreover, the N-terminal SRCR repeats domain is more catalytically active than the C-terminal oxidase domain. Thus, LOX is the third family of lysine deacetylases in addition to histone deacetylase and sirtuin families. In this review, we discuss how the LOX family targets different cellular proteins for deacetylation and deacetylimination to control the development and metastasis of cancer.
Abstract IA007: Targeting the hypoxia-induced DDR to improve radiotherapy response
Authors: Ester Hammond
Journal: Cancer Research (2024)

Abstract Regions of hypoxia (insufficient oxygen) occur to some extent in most if not all solid tumors. Within hypoxic regions the levels of oxygen are heterogeneous and can reach near anoxic levels, often referred to as radiobiological hypoxia. Cells experiencing radiobiological hypoxia are significantly more resistant to radiation-induced DNA damage and negatively impact radiotherapy response. A number of clinical studies have demonstrated that hypoxia is a significant indicator of poor patient response. Radiobiological hypoxia, unlike milder hypoxic conditions, leads to a robust DNA damage response although interestingly, this occurs in the absence of detectable DNA damage. Instead, the hypoxia-induced DDR has been attributed to the accumulation of replication stress. Previously, we demonstrated that hypoxia-induced replication stress originated from reduced nucleotide availability due to the oxygen-dependency of ribonucleotide reductase. More, recently we have implicated the accumulation of R-loops in contributing to not only the hypoxia-induced DDR but also transcriptional stress. Numerous factors play key roles in maintaining R-loops and preventing the accumulation of DNA damage including the DNA/RNA helicase SETX. Using SETX has an exemplar, we have demonstrated that targeting R-loop factors leads to increased DNA damage in hypoxic conditions. Currently, we are testing the hypothesis that hypoxia specific R-loop factors are potential therapeutic targets which offer the possibility of increasing the radiosensitivity of hypoxic cells. Citation Format: Ester Hammond. Targeting the hypoxia-induced DDR to improve radiotherapy response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA007.
A 23-Gene Prognostic Index Predicts Progression and Bacillus Calmette-Guérin Response in Non–muscle-invasive Bladder Cancer
Authors: Seon-Kyu Kim, Young Joon Byun, Seong-Hwan Park, Xuan-Mei Piao, Chuang-Ming Zheng, Seongmin Moon, Kyeong Kim, Sun Jin Song, Ho Won Kang, Won Tae Kim, Ok-Jun Lee, Yung Hyun Choi, Sung-Kwon Moon, Wun-Jae Kim, Young Deuk Choi, Seon-Young Kim, Seok Joong Yun
Journal: European Urology (2024)
Abstract A012: Mre11 mediates cGAS activation and tumor suppression through ZBP1-dependent necroptosis in breast cancer
Authors: Minguk Jo, Rashmi J. Kumar, Chien-Chu Lin, Joshua A. Boyer, Jamshaid A. Shahir, Katerina Fagan-Solis, Dennis A. Simpson, Cheng Fan, Christine E. Foster, Anna M. Goddard, Lynn M. Lerner, Simon W. Ellington, Qinhong Wang, Ying Wang, Alice Y. Ho, Pengda Liu, Charles M. Perou, Qi Zhang, Robert K. McGinty, Jeremy E. Purvis, Gaorav P. Gupta
Journal: Cancer Research (2024)

Abstract Oncogene-induced replication stress leads to endogenous DNA damage, activating the cGAS/STING signaling pathway, a critical player in tumor suppression. The exact mechanism underlying cGAS activation, however, remains unclear due to the continual inhibition of cGAS by its high-affinity interaction with the histone acidic patch (AP), which sterically prevents its activation by double-stranded DNA (dsDNA). In this investigation, we elucidate the significant role of the DNA double-strand break sensor, Mre11, in regulating cGAS activation and thereby inhibiting mammary tumorigenesis. Our data reveal that the binding of the Mre11-Rad50-Nbn (MRN) complex to nucleosome fragments is crucial to liberate cGAS from AP-mediated sequestration, facilitating its subsequent activation by dsDNA. Consequently, Mre11 emerges as a vital component in the cGAS activation process, responding to oncogenic stress, cytosolic dsDNA, and ionizing radiation. Moreover, we highlight the ramifications of Mre11-dependent cGAS activation which fosters ZBP1/RIPK3/MLKL-mediated necroptosis, a vital process in curtailing oncogenic proliferation and breast tumorigenesis. Significantly, our study identifies a strong correlation between the downregulation of ZBP1 in human triple-negative breast cancer and increased genomic instability, suppressed immune response, and adverse patient prognosis. Our findings firmly establish Mre11 as a pivotal mediator connecting DNA damage to cGAS activation, thereby facilitating tumor suppression through ZBP1-dependent necroptosis, offering a promising avenue for targeted breast cancer therapies. Citation Format: Minguk Jo, Rashmi J. Kumar, Chien-Chu Lin, Joshua A. Boyer, Jamshaid A. Shahir, Katerina Fagan-Solis, Dennis A. Simpson, Cheng Fan, Christine E. Foster, Anna M. Goddard, Lynn M. Lerner, Simon W. Ellington, Qinhong Wang, Ying Wang, Alice Y. Ho, Pengda Liu, Charles M. Perou, Qi Zhang, Robert K. McGinty, Jeremy E. Purvis, Gaorav P. Gupta. Mre11 mediates cGAS activation and tumor suppression through ZBP1-dependent necroptosis in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A012.
Abstract IA011: Polymerase-based bypass of atypical UV photoproducts
Authors: Steven A. Roberts
Journal: Cancer Research (2024)

Abstract UV light is a ubiquitous environmental mutagen that is an etiological cause of skin cancers like melanoma. While the genomes of human cutaneous melanomas have high mutation burdens primarily consisting of C to T substitutions in TC and CC dinucleotides (consistent with cyclobutane pyrimidine dimer formation), many of the driver mutations contributing to disease progression involve other types of substitutions at non-dipyrimidine sequences. Our whole genome sequencing of UVB or UVC irradiated yeast has revealed non-canonical UV induced substitution types. These mutations included TA to TT and AC to TT substitutions that commonly occur as activating BRAF mutations in human melanomas. UV treatment and sequencing of deletion mutants of DNA polymerase eta, the protein mutated in human XPV patients, indicated that this polymerase does not impact TA to TT mutagenesis, but contributes to the formation of AC to TT substitutions. Surprisingly, loss of pol eta revealed additional CA to AA substitutions, highlighting another UV-induced mutation class possibly created by a non-canonical photoproduct. All novel mutation classes in pol eta deficient yeast displayed transcriptional asymmetry, consistent with the repair of the cognate lesion by transcription-coupled nucleotide excision repair. However, UV-induced mutations lacked replication asymmetry in both wild type and rad30Δ yeast, suggesting TLS occurs nearly equally on leading and lagging strands. Both TA to TT and AC to TT substitutions were dependent on DNA polymerase zeta, and altered by a mutant of DNA polymerase epsilon, suggesting the involvement of both TLS and replicative polymerases in UV-induced mutagenesis. These results emphasize the importance of non-canonical UV lesions in driving melanomagenesis, provide mechanisms of how these lesions result in mutations, and suggest the variable accuracy of TLS polymerases across from atypical UV photoproducts may alter the trajectory of skin cancer evolution in XPV patients. Citation Format: Steven A. Roberts. Polymerase-based bypass of atypical UV photoproducts [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA011.