Multiomic Analysis Identifies a High-Risk Metabolic and TME Depleted Signature that Predicts Early Clinical Failure in DLBCL.

PURPOSE: 60-70% of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients avoid events within 24 months of diagnosis (EFS24) and the remainder have poor outcomes. Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. PATIENTS AND METHODS: Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis followed by integration with clinical and genomic data was used to identify a multiomic signature associated with high risk of early clinical failure. RESULTS: Current DLBCL classifiers are unable to discriminate cases who fail EFS24. We identified a high risk RNA signature that had a hazard ratio (HR, 18.46 [95% CI 6.51-52.31] P < .001) in a univariate model, which did not attenuate after adjustment for age, IPI and COO (HR, 20.8 [95% CI, 7.14-61.09] P < .001). Further analysis revealed the signature was associated with metabolic reprogramming and a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. CONCLUSION: This novel and integrative approach is the first to identify a signature at diagnosis that will identify DLBCL at high risk for early clinical failure and may have significant implications for design of therapeutic options.

Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.

Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.

Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway.

Multiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, it's unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H 2 O 2 sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H 2 O 2 . Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H 2 O 2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.

Adverse events from nitrate administration during right ventricular myocardial infarction: a systematic review and meta-analysis.

BACKGROUND: The current guidelines of the American Heart Association (AHA) and European Society of Cardiology (ESC) recommend that when right ventricular myocardial infarction (RVMI) is present patients are not administered nitrates, due to the risk that decreasing preload in the setting of already compromised right ventricular ejection fraction may reduce cardiac output and precipitate hypotension. The cohort study (n=40) underlying this recommendation was recently challenged by new studies suitable for meta-analysis (cumulatively, n=1050), suggesting that this topic merits systematic review. METHODS: The protocol was registered on PROSPERO and published in Evidence Synthesis. Six databases were systematically searched in May 2022: PubMed, Embase, MEDLINE Complete, Cochrane CENTRAL Register, CINAHL and Google Scholar. Two investigators independently assessed for quality and bias and extracted data using Joanna Briggs Institute tools and methods. Risk ratios and 95% CIs were calculated, and meta-analysis performed using the random effects inverse variance method. RESULTS: Five studies (n=1113) were suitable. Outcomes included haemodynamics, GCS, syncope, arrest and death. Arrest and death did not occur in the RVMI group. Meta-analysis was possible for sublingual nitroglycerin 400 µg (2 studies, n=1050) and found no statistically significant difference in relative risk to combined inferior and RVMI at 1.31 (95% CI 0.81 to 2.12, p=0.27), with an absolute effect of 3 additional adverse events per 100 treatments. Results remained robust under sensitivity analysis. CONCLUSIONS: This review suggests that the AHA and ESC contraindications are not supported by evidence. Key limitations include all studies having concomitant inferior and RVMI, not evaluating beneficial effects and very low certainty of evidence. As adverse events are transient and easily managed, nitrates are a reasonable treatment modality to consider during RVMI on current evidence. PROSPERO REGISTRATION NUMBER: CRD42020172839.

Adverse events from nitrate administration during right ventricular myocardial infarction: a systematic review protocol.

OBJECTIVE: This systematic review will aim to summarize and evaluate the literature describing the evidence regarding adverse events from the administration of nitrates during right ventricular myocardial infarction. INTRODUCTION: Withholding nitrates in the setting of right ventricular myocardial infarction is currently recommended by the American Heart Association, European Society of Cardiology, and in the Australian Journal of General Practice, due to the risk that decreasing preload in the setting of already compromised right ventricular ejection fraction may reduce cardiac output and precipitate hypotension or exacerbate cardiogenic shock. The original evidence from 1989 underpinning these recommendations displays methodological weaknesses including low sample size and confounding interventions. More recent and comprehensive research from 2014, 2016, 2018, and 2019 conflicts with the conclusions from the 1989 study, suggesting instead that nitrate administration during right ventricular myocardial infarction results in no significant difference in the rate of adverse events. The combination of recommended practice based on 30-year-old evidence and the emergence of recent challenging evidence suggest that this topic merits systematic review. INCLUSION CRITERIA: The study will include both experimental and observational (descriptive and analytical) study designs that discuss the occurrence of adverse events from the administration of nitrates during a known right ventricular myocardial infarction. METHODS: Six databases will be systematically searched: the Cochrane CENTRAL Register, PubMed, Embase, MEDLINE Complete, CINAHL, and Google Scholar. Identified studies will be independently assessed for inclusion by two investigators using JBI critical appraisal tools. Data will be extracted for narrative and tabular synthesis. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42020172839.

Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy.

Cancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.