bluuebunny/crossref_metadata_2025_split huggingface dataset:
The oral administration of
Lacticaseibacillus casei
Shirota alleviates acetaminophen-induced liver injury through accelerated acetaminophen metabolism via the liver-gut axis in mice
Authors: Lv Longxian , Ren Siqi , Jiang Huiyong , Yan Ren , Chen Wenyi , Yan Ruiyi , Dong Jinming , Shao Li , Yu Ying 
Published: January 2024

ABSTRACT

Acetaminophen is a widely used antipyretic and analgesic drug, and its overdose is the leading cause of drug-induced acute liver failure. This study aimed to investigate the effect and mechanism of
Lacticaseibacillus casei
Shirota (LcS), an extensively used and highly studied probiotic, on acetaminophen-induced acute liver injury. C57BL/6 mice were gavaged with LcS suspension or saline once daily for 7 days before acute liver injury was induced via intraperitoneal injection of 300 mg/kg acetaminophen. The results showed that LcS significantly decreased acetaminophen-induced liver and ileum injury, as demonstrated by reductions in the increases in aspartate aminotransferase, total bile acids, total bilirubin, indirect bilirubin, and hepatic cell necrosis. Moreover, LcS alleviated acetaminophen-induced intestinal mucosal permeability, decreased serum IL-1α and lipopolysaccharide levels, and elevated serum eosinophil chemokine (eotaxin) and hepatic glutathione levels. Furthermore, analysis of the gut microbiota and metabolome showed that LcS reduced the acetaminophen-enriched levels of
Cyanobacteria
,
Oxyphotobacteria
, long-chain fatty acids, cholesterol, and sugars in the gut. Additionally, the transcriptomic and proteomic results showed that LcS mitigated the decrease in metabolic and immune pathways as well as glutathione formation during acetaminophen-induced acute liver injury. This is the first study showing that pretreatment with LcS alleviates acetaminophen-enriched acute liver injury, and it provides a reference for the application of LcS.

IMPORTANCE

Acetaminophen is the most frequently used antipyretic analgesic worldwide. As a result, overdoses easily occur and lead to drug-induced acute liver injury, which quickly progresses to liver failure with a mortality of 60%–80% if not corrected in time. The current emergency treatment for overused acetaminophen needs to be administered within 8 hours to avoid liver injury or even liver failure. Therefore, developing preventive strategies for liver injury during planned acetaminophen medication is particularly important, preferably nonpharmacological methods.
Lacticaseibacillus casei
Shirota (LcS) is a famous probiotic that has been used for many years. Our study found that LcS significantly alleviated acetaminophen-induced acute liver injury, especially acetaminophen-induced liver injury toward fulminant hepatic failure. Here, we elucidated the function and potential mechanisms of LcS in alleviating acetaminophen-induced acute liver injury, hoping it will provide preventive strategies to people during acetaminophen treatment.
Rapid nanopore sequencing and predictive susceptibility testing of positive blood cultures from intensive care patients with sepsis
Authors: Harris Patrick N. A. , Bauer Michelle J. , Lüftinger Lukas , Beisken Stephan , Forde Brian M. , Balch Ross , Cotta Menino , Schlapbach Luregn , Raman Sainath , Shekar Kiran , Kruger Peter , Lipman Jeff , Bialasiewicz Seweryn , Coin Lachlan , Roberts Jason A. , Paterson David L. , Irwin Adam D. 
Published: January 2024

ABSTRACT

We aimed to evaluate the performance of Oxford Nanopore Technologies (ONT) sequencing from positive blood culture (BC) broths for bacterial identification and antimicrobial susceptibility prediction. Patients with suspected sepsis in four intensive care units were prospectively enrolled. Human-depleted DNA was extracted from positive BC broths and sequenced using ONT (MinION). Species abundance was estimated using Kraken2, and a cloud-based system (AREScloud) provided
in silico
predictive antimicrobial susceptibility testing (AST) from assembled contigs. Results were compared to conventional identification and phenotypic AST. Species-level agreement between conventional methods and AST predicted from sequencing was 94.2% (49/52), increasing to 100% in monomicrobial infections. In 262 high-quality AREScloud AST predictions across 24 samples, categorical agreement (CA) was 89.3%, with major error (ME) and very major error (VME) rates of 10.5% and 12.1%, respectively. Over 90% CA was achieved for some taxa (e.g.,
Staphylococcus aureus
) but was suboptimal for
Pseudomonas aeruginosa
. In 470 AST predictions across 42 samples, with both high quality and exploratory-only predictions, overall CA, ME, and VME rates were 87.7%, 8.3%, and 28.4%. VME rates were inflated by false susceptibility calls in a small number of species/antibiotic combinations with few representative resistant isolates. Time to reporting from sequencing could be achieved within 8–16 h from BC positivity. Direct sequencing from positive BC broths is feasible and can provide accurate predictive AST for some species. ONT-based approaches may be faster but significant improvements in accuracy are required before it can be considered for clinical use.

IMPORTANCE
Sepsis and bloodstream infections carry a high risk of morbidity and mortality. Rapid identification and susceptibility prediction of causative pathogens, using Nanopore sequencing direct from blood cultures, may offer clinical benefit. We assessed this approach in comparison to conventional phenotypic methods and determined the accuracy of species identification and susceptibility prediction from genomic data. While this workflow holds promise, and performed well for some common bacterial species, improvements in sequencing accuracy and more robust predictive algorithms across a diverse range of organisms are required before this can be considered for clinical use. However, results could be achieved in timeframes that are faster than conventional phenotypic methods.
Temporal development and potential interactions between the gut microbiome and resistome in early childhood
Authors: Zhao Lanlan , Yang Xiao , Liang Yijia , Zhang Ziyi , Ding Yanwen , Wang Yihui , Chen Bin , Wu Jiacheng , Jin Chuandi , Zhao Guoping , Li Ziyun , Zhang Lei 
Published: January 2024

ABSTRACT
Antimicrobial resistance-associated infections have become a major threat to global health. The gut microbiome serves as a major reservoir of bacteria with antibiotic resistance genes; whereas, the temporal development of gut resistome during early childhood and the factors influencing it remain unclear. Moreover, the potential interactions between gut microbiome and resistome still need to be further explored. In this study, we found that antibiotic treatment led to destabilization of the gut microbiome and resistome structural communities, exhibiting a greater impact on the resistome than on the microbiome. The composition of the gut resistome at various developmental stages was influenced by the abundance and richness of different core microbes. First exposure to antibiotics led to a dramatic increase in the number of opportunistic pathogens carrying multidrug efflux pump encoding genes. Multiple factors could influence the gut microbiome and resistome formation. The data may provide new insights into early-life research.

IMPORTANCE
In recent years, the irrational or inappropriate use of antibiotics, an important life-saving medical intervention, has led to the emergence and increase of drug-resistant and even multidrug-resistant bacteria. It remains unclear how antibiotic exposure affects various developmental stages of early childhood and how gut core microbes under antibiotic exposure affect the structural composition of the gut resistome. In this study, we focused on early antibiotic exposure and analyzed these questions in detail using samples from infants at various developmental stages. The significance of our research is to elucidate the impact of early antibiotic exposure on the dynamic patterns of the gut resistome in children and to provide new insights for early-life studies.
Abstract A006: Targeting SETD2 in combination with radiotherapy in rectal cancer
Authors: Akana Lokesh , Rodrigues Henrique , Zuniga Oscar , Wolfe Adam R. 
Published: January 2024

Abstract
Purpose: Tri-methyl-histone H3 (Lys36) is a modification of histone H3 involved in gene regulation and chromatin organization. It plays a crucial role in cell response to ionizing radiation and affects DNA damage repair, with altered levels linked to decreased radiation sensitivity. We hypothesize that targeting SETD2, the histone methyltransferase responsible for adding the tri-methyl group to Lys36 of histone H3, may enhance radiosensitivity in rectal cancer cells. Methods: To understand the role of Tri-Methyl-Histone H3 (Lys36) in response to ionizing radiation (IR), clonogenic assays, γH2aX foci staining, and western blot analysis of DNA damage response proteins and histones were performed on two established human rectal cancer cell lines following either RNA inhibition (RNAi) or drug targeting of SETD2, EPZ-719. Results: After treating two colorectal cancer cell lines (LS123 and LoVo) with IR (5 Gy) in vitro, Tri-Methyl-Histone H3 (Lys36) levels increased. When combined with IR, SETD2 RNAi reduced Tri-Methyl-Histone H3 (Lys36) and decreased clonogenic survival and cell proliferation. In vitro treatment with a novel SETD2 inhibitor, EPZ-719, increased DNA damage following IR (5 Gy) as measured by γH2aX foci staining. The treatment with EPZ-719 showed an enhancement in radiosensitization with a 0.37 improvement in the dose enhancement ratio. Conclusion: Our preclinical data indicates that targeting SETD2 to reduce Tri-Methyl-Histone H3 (Lys36) mediated DNA repair could improve the efficacy of radiation therapy for rectal cancer patients.
Citation Format: Lokesh Akana, Henrique Rodrigues, Oscar Zuniga, Adam R. Wolfe. Targeting SETD2 in combination with radiotherapy in rectal 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 A006.
Abstract A018: GRB2 acts at reversed forks in the BRCA2-RAD51-MRE11 axis: a therapeutic target and enabling predictive biomarker for PARP inhibitor-immunotherapy combination
Authors: Tainer John A. , Schlacher Katharina , Wang Bin , Peng Guang , Ahmed Zamal 
Published: January 2024

Abstract
Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adaptor for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS–STING pathway to trigger pro-inflammatory cytokine production. Moreover, in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment reduced tumor burden and enabled high survival consistent with immune suppression of cancer growth. Collective findings unveil GRB2 function and mechanism for fork protection in the BRCA2-RAD51-MRE11 axis and suggest GRB2 as a potential therapeutic target and an enabling predictive biomarker for patient selection for PARPi and immunotherapy combination.
Citation Format: John A. Tainer, Katharina Schlacher, Bin Wang, Guang Peng, Zamal Ahmed. GRB2 acts at reversed forks in the BRCA2-RAD51-MRE11 axis: a therapeutic target and enabling predictive biomarker for PARP inhibitor-immunotherapy combination [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 A018.
Abstract A027: Development of small molecule inhibitors of the Ku-DNA interaction: Impacts on NHEJ, DDR signaling, optimizing genome editing technologies, and therapeutic intervention for the treatment of cancer
Authors: Turchi John J. , Mendoza-Munoz Pamela L. , VanderVere-Carozza Pamela S. , Gavande Navnath S. , Dynlacht Joseph R. , Garrett Joy E. , Chauhan Dineshsinha , Pawelczak Katherine S. 
Published: January 2024

Abstract
DNA-PK, the DNA-dependent protein kinase is a validated target for cancer therapeutics that drives the DNA damage response (DDR) and plays a critical role in the non-homologous end joining (NHEJ) DNA repair pathway. NHEJ is responsible for the repair of DNA double strand breaks (DSB), particularly those induced by ionizing radiation (IR). The generation of DNA DSBs drives clinical efficacy of radiation therapy and numerous DNA damaging chemotherapeutic drugs used to treat cancer. Modulating the DSB repair pathways is an effective mechanism to increase clinical efficacy of IR and certain chemotherapeutic regimens. We have taken the novel approach to inhibit target the DDR and NHEJ by developing small molecule inhibitors of the DSB sensor Ku, and its interaction with DNA. The Ku heterodimer serves as initiator of the NHEJ pathway following DSB induction and is the key DNA-binding component of the DNA-PK. We have created an extensive library of Ku DNA binding inhibitors (Ku-DBis) and demonstrate a direct interaction with the Ku heterodimer and potent inhibition of Ku-DNA binding and DNA-PK catalytic activity. In vitro analysis of a series of Ku truncation mutants defines the necessary domains for Ku-DBi activity. Ku-DBi’s show potent inhibition of in vitro and cellular NHEJ and, as a result, potentiate cellular sensitivity to DSB-inducing agents. Enhancement of sensitivity is a function of inhibiting DNA-PKcs autophosphorylation and dysregulation of signaling to the DDR. Recent chemical optimization has identified independent pharmacophores that drive off-target cytotoxicity, direct Ku inhibitory potency, and enhance cellular uptake activity. These data served as the basis for creation of a novel series of Ku-DBi’s towards interrogating NHEJ and DDR signaling in vivo, optimizing genome editing technologies, and therapeutic intervention for the treatment of cancer.
Citation Format: John J. Turchi, Pamela L. Mendoza-Munoz, Pamela S. VanderVere-Carozza, Navnath S. Gavande, Joseph R. Dynlacht, Joy E. Garrett, Dineshsinha Chauhan, Katherine S. Pawelczak. Development of small molecule inhibitors of the Ku-DNA interaction: Impacts on NHEJ, DDR signaling, optimizing genome editing technologies, and therapeutic intervention for the treatment of 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 A027.
Abstract A033: The ING5 epigenetic reader regulates a subset of DNA repair genes to maintain genomic integrity
Authors: Dantas Arthur E , Al-Shueili Buthaina , Djamshidi Mahbod , Riabowol Karl 
Published: January 2024

Abstract
The ING family of epigenetic histone code readers (ING1-5) recognize the H3K4Me3 epigenetic mark to target histone acetyltransferase (HAT) or histone deacetylase (HDAC) complexes to regulate local acetylation levels and affect transcription. We and others have shown that ING5 promotes stem cell character in normal and in cancer stem cells and that loss of ING5 promotes stem cell differentiation. Examination of an ING5 knockout (KO) mouse model showed increased levels of DNA damage in different tissues, and particularly in the male germ line. ING5 mouse embryo fibroblasts (MEFs) also show a &gt;2-fold increase in cells containing gH2AX foci in the absence of exogenous DNA damaging agents. Examining the transcriptomes of ING5 KO and wild-type littermate MEFs indicates that several genes encoding key DNA repair proteins such as those acting in homologous recombination (BRCA1 and BRCA2) and base excision repair (PARP1) are repressed several-fold and ING5 KO MEFs show increased sensitivity to the PARP inhibitor olaparib. Given that ING5 functions to help maintain stem cell character in normal and in cancer stem cells, we propose that ING5 serves a role in maintaining a high level of DNA repair capability in stem cell populations to preserve genomic integrity.
Citation Format: Arthur E Dantas, Buthaina Al-Shueili, Mahbod Djamshidi, Karl Riabowol. The ING5 epigenetic reader regulates a subset of DNA repair genes to maintain genomic integrity [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 A033.
Abstract B014: KDM4B mutations in human cancers
Authors: Bush Wesley A. , Petreaca Ruben C. 
Published: January 2024

Abstract
Homology-dependent-repair (HDR) is an essential process for the error-free correction of double-strand-breaks (DSBs). The histone demethylase KDM4B plays a role in the HDR repair process, wherein its H3K9 demethylase activity aids recruitment of repair factors such as the ATM checkpoint activator and KAT5 histone acetyltransferase and remodeler to the break site. Inhibition of KDM4B has been shown to disrupt the recruitment of ATM, and KAT5, affecting other downstream HDR factors and leading to widespread unrepaired DNA damage. Both over- and under-expression of KDM4B have implications for cancer severity, and changes in KDM4B expression have been shown to affect the expression of other oncogenes outside of the HDR pathway. We performed a pan-cancer analysis of the effects of KDM4B alterations in human cancers using data from the Catalogue of Somatic Mutations in Cancers (COSMIC). We find that KDM4B mutations occur in nearly every cancer. Further, there is a tendency of co-occurring mutations between KDM4B and several HDR genes the most significant being BRCA2. Machine learning tools did not predict any of the observed KDM4B mutations to be drivers. Our data suggests that although KDM4B does not display a driver phenotype it contributes to the destabilization of DNA damage repair machinery that causes cellular transformation and immortalization.
Citation Format: Wesley A. Bush, Ruben C. Petreaca. KDM4B mutations in human cancers [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 B014.
Abstract IA010: Molecular archeology of cancer
Authors: Van Loo Peter 
Published: January 2024

Abstract
Tumor development is driven by changes to the genome leading to fitness advantages underlying successive clonal expansions. As somatic changes occur across most or all cell cycles, the cancer genome carries an archeological record of its past. Over the past years, we have developed several approaches to mine that archeological record from the cancer genome, which we collectively call 'molecular archeology of cancer'. Using these approaches, we are able to infer the subclonal architecture of tumors and gain key insights into the order and timing of the genomic changes that occurred over their evolutionary history. We have applied these approaches in a large-scale pan-cancer setting, showing that intra-tumor heterogeneity is pervasive across cancers and that the timelines of tumor evolution span multiple years to decades. Key driver events in tumor evolution typically occur early, and copy number gains often accumulate as punctuated bursts, commonly after genome doubling. Late genome doubling is frequent in cancer evolution and is typically followed by an increase in the rate of copy number gains. Genome duplications affect the selection landscape of copy number losses, while only minimally impacting copy number gains. Extending our timing framework to time mutational signatures, we find that, as expected, environmentally associated mutations are associated with early tumor development. We also find evidence of episodic APOBEC mutagenesis across many tumors and clear timing patterns in many mutational processes that have unknown origins. Our approaches increase the evolutionary information that can be obtained from tumor genome sequences and, therefore, improve our understanding of the developmental history of cancer.
Citation Format: Peter Van Loo. Molecular archeology of 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 IA010.
Abstract IA011: Polymerase-based bypass of atypical UV photoproducts
Authors: Roberts Steven A. 
Published: January 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.