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Kristijan Ramadan's group have published a new paper which shows how cells keep the DNA replication machinery moving when faced with blockers.
Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor initiating cells.
Similar to tumor initiating cells (TICs), minimal residual disease (MRD) is capable of re-initiating tumors and causing recurrence. However, the molecular characteristics of solid tumor MRD cells and drivers of their survival have remained elusive. Here we performed dense multi-region transcriptomics analysis of paired biopsies from 17 ovarian cancer patients before and after chemotherapy. We reveal that while MRD cells share important molecular signatures with TICs, they are also characterized by an adipocyte-like gene expression signature and a portion of them had undergone epithelial-mesenchymal transition (EMT). In a cell culture MRD model, MRD-mimic cells show the same phenotype and are dependent on fatty acid oxidation for survival and resistance to cytotoxic agents. These findings identify EMT and FAO as attractive targets to eradicate MRD in ovarian cancer and make a compelling case for the further testing of FAO inhibitors in treating MRD.
In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer.
PURPOSE: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer. EXPERIMENTAL DESIGN: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial (n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer. RESULTS: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer. CONCLUSIONS: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.
Eukaryotic topoisomerase 1 (TOP1) regulates DNA topology to ensure efficient DNA replication and transcription. TOP1 is also a major driver of endogenous genome instability, particularly when its catalytic intermediate-a covalent TOP1-DNA adduct known as a TOP1 cleavage complex (TOP1cc)-is stabilised. TOP1ccs are highly cytotoxic and a failure to resolve them underlies the pathology of neurological disorders but is also exploited in cancer therapy where TOP1ccs are the target of widely used frontline anti-cancer drugs. A critical enzyme for TOP1cc resolution is the tyrosyl-DNA phosphodiesterase (TDP1), which hydrolyses the bond that links a tyrosine in the active site of TOP1 to a 3' phosphate group on a single-stranded (ss)DNA break. However, TDP1 can only process small peptide fragments from ssDNA ends, raising the question of how the ~90 kDa TOP1 protein is processed upstream of TDP1. Here we find that TEX264 fulfils this role by forming a complex with the p97 ATPase and the SPRTN metalloprotease. We show that TEX264 recognises both unmodified and SUMO1-modifed TOP1 and initiates TOP1cc repair by recruiting p97 and SPRTN. TEX264 localises to the nuclear periphery, associates with DNA replication forks, and counteracts TOP1ccs during DNA replication. Altogether, our study elucidates the existence of a specialised repair complex required for upstream proteolysis of TOP1ccs and their subsequent resolution.
This book is ideal for pharmaceutical companies as they develop novel targets using sirtuins for metabolic diseases, cancer and neurodegenerative illnesses. Sirtuins are a diverse family of proteins, with several members in mammals.
Conventional static culture fails to replicate the physiological conditions that exist in vivo. Recent advances in biomedical engineering have resulted in the creation of novel dynamic culturing systems that permit the recapitulation of normal physiological processes ex vivo. Whilst the physiological benefit for its use in the culture of two-dimensional cellular monolayer has been validated, its role in the context of primary human tissue culture has yet to be determined. This systematic review identified 22 articles that combined dynamic physiological culture techniques with primary human tissue culture. The most frequent method described (55%) utilised dynamic perfusion culture. A diverse range of primary human tissue was successfully cultured. The median duration of successful ex vivo culture of primary human tissue for all articles was eight days; however, a wide range was noted (5 h–60 days). Six articles (27%) reported successful culture of primary human tissue for greater than 20 days. This review illustrates the physiological benefit of combining dynamic culture with primary human tissue culture in both long-term culture success rates and preservation of native functionality of the tissue ex vivo. Further research efforts should focus on developing precise biochemical sensors that would allow for real-time monitoring and automated self-regulation of the culture system in order to maintain homeostasis. Combining these techniques allows the creation of an accurate system that can be used to gain a greater understanding of human physiology.
Neutralization of PD-L2 is Essential for Overcoming Immune Checkpoint Blockade Resistance in Ovarian Cancer.
PURPOSE: Ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB), with reported low patient response rates. We found that the immune checkpoint ligand PD-L2 is robustly expressed in patient samples of ovarian cancers and other malignancies exhibiting suboptimal response to ICB but not in cancers that are ICB sensitive. Therefore we hypothesize that PD-L2 can facilitate immune escape from ICB through incomplete blockade of the PD-1 signaling pathway. EXPERIMENTAL DESIGN: We engineered a soluble form of the PD-1 receptor (sPD-1) capable of binding and neutralizing both PD-L2 and PD-L1 with x200 and x10,000 folds improvement in binding affinity over wild-type PD-1. Leading to superior inhibition of ligand-mediated PD-1 activities. RESULTS: Both In vitro and in vivo analyses performed in this study demonstrated that the high-affinity sPD-1 molecule is superior at blocking both PD-L1 and PD-L2 mediated immune evasion and reducing tumor growth in immune-competent murine models of ovarian cancer. CONCLUSIONS: The data presented in this study provides justification for using a dual targeting, high-affinity sPD-1 receptor as an alternative to PD-1 or PD-L1 therapeutic antibodies for achieving superior therapeutic efficacy in cancers expressing both PD-L2 and PD-L1.
Appendicitis risk prediction models in children presenting with right iliac fossa pain (RIFT study): a prospective, multicentre validation study.
BACKGROUND: Acute appendicitis is the most common surgical emergency in children. Differentiation of acute appendicitis from conditions that do not require operative management can be challenging in children. This study aimed to identify the optimum risk prediction model to stratify acute appendicitis risk in children. METHODS: We did a rapid review to identify acute appendicitis risk prediction models. A prospective, multicentre cohort study was then done to evaluate performance of these models. Children (aged 5-15 years) presenting with acute right iliac fossa pain in the UK and Ireland were included. For each model, score cutoff thresholds were systematically varied to identify the best achievable specificity while maintaining a failure rate (ie, proportion of patients identified as low risk who had acute appendicitis) less than 5%. The normal appendicectomy rate was the proportion of resected appendixes found to be normal on histopathological examination. FINDINGS: 15 risk prediction models were identified that could be assessed. The cohort study enrolled 1827 children from 139 centres, of whom 630 (34·5%) underwent appendicectomy. The normal appendicectomy rate was 15·9% (100 of 630 patients). The Shera score was the best performing model, with an area under the curve of 0·84 (95% CI 0·82-0·86). Applying score cutoffs of 3 points or lower for children aged 5-10 years and girls aged 11-15 years, and 2 points or lower for boys aged 11-15 years, the failure rate was 3·3% (95% CI 2·0-5·2; 18 of 539 patients), specificity was 44·3% (95% CI 41·4-47·2; 521 of 1176), and positive predictive value was 41·4% (38·5-44·4; 463 of 1118). Positive predictive value for the Shera score with a cutoff of 6 points or lower (72·6%, 67·4-77·4) was similar to that of ultrasound scan (75·0%, 65·3-83·1). INTERPRETATION: The Shera score has the potential to identify a large group of children at low risk of acute appendicitis who could be considered for early discharge. Risk scoring does not identify children who should proceed directly to surgery. Medium-risk and high-risk children should undergo routine preoperative ultrasound imaging by operators trained to assess for acute appendicitis, and MRI or low-dose CT if uncertainty remains. FUNDING: None.