EpOMEs suppress excessive and unnecessary immune responses at late infection stage in insects. This immune resolvin activity of EpOMEs includes the cell lysis of hemocytes by causing apoptosis. This cytolytic toxicity of EpOMEs suggests a potential insecticidal activity of their stable analogs. In fact, a propoxy derivative of 12,13-EpOME called AS56 mimicked EpOME activity by suppressing immune responses and exhibited insecticidal activity against a lepidopteran insect, Spodoptera exigua. This study evaluated the potency of the EpOME analogs by modifying their functional groups. PD28 is a racemic mixture of propoxy analog at the twelfth carbon. FD25 is a racemic butoxy mixture at the twelfth carbon of AS56. AS61 is saturated at the ninth carbon of AS56. The effects of the EpOME analogs were assessed on two cellular immune responses: hemocyte-spreading and nodule formation. All four analogs inhibited the cellular immune responses; however, AS56 was the most potent in inhibiting the immune responses. FD25 and AS61 were significantly less potent compared to AS56, suggesting crucial roles of the double bond at the ninth carbon and the propoxy chain at the twelfth carbon. The stronger inhibitory activity of AS56 compared to PD28 also suggests the functional role of the stereoisomeric form in physiological functions. The cytotoxicity of AS56 was also the most potent among the analogs, suggesting its insecticidal activity. Subsequent insecticidal bioassays on AS56 toxicity were performed against different insect species. These EpOME analogs were potent against lepidopteran insects (S. exigua and Plutella xylostella) but not against coleopteran (Tenebrio molitor) or thysanopteran (Frankliniella occidentalis) species. Among the EpOME analogs, AS56 was the most toxic against the lepidopteran insects. Spraying AS56 in cabbage fields infested by lepidopteran insects led to acute and high control efficacy against two lepidopteran pests, similar to that of a chemical insecticide, fluxametamide. The AS56-intoxicated larvae exhibited over-excitation in their behavior around 12 h post-treatment. This study indicates that AS56 exhibits an oral toxicity against lepidopteran insects with its cytotoxicity and behavioral over-excitation.

Despite intriguing roles for the Succinate receptor (Sucnr1) in inflammation, few studies have explored its role in hematopoiesis. Here, we show that low SUCNR1 represents a marker for reduced overall and progression-free survival in acute myeloid leukemia (AML) patients. Succinic acid, which displays Sucnr1-dependent and independent effects, promotes disease in mouse models of pre-leukemic myelopoiesis, AML and AML xenografts, expressing low SUCNR1. In vivo global or hematopoietic deletion of Sucnr1 induces expansion of hematopoietic stem and progenitor cells (HSPC) and hematopoiesis, whilst Sucnr1-tomato+ HSPC display restricted engraftment potential. Mechanistically, activation of Sucnr1 counterbalances the stimulatory effect of intracellular succinate in HSPC and preserves HSPC transcriptional programs via control of S100a8/S100a9. Blocking S100a9 with tasquinimod rescues the defects of Sucnr1 knock-out mice, and combined with a potent Sucnr1 agonist shows therapeutic value in AML mice. In AML xenografts, single-cell RNA-sequencing reanalyses confirm SUCNR1 as a therapeutic vulnerability in patients. Together, Sucnr1 signaling restricts hematopoiesis at least partially through HSPC and via control of S100a8/S100a9. Its dysregulation emerges as contributor to malignancy that opens therapeutic avenues for AML patients.

Polyunsaturated methoxylated ether lipids display a range of potentially important biological properties, yet their mechanism of action remain poorly understood due to the difficulty of isolating pure material from natural sources. Herein, a novel synthetic approach to form a docosahexaenoic acid (DHA)-like methoxylated ether lipid is reported. By utilising a modular semi-synthetic approach, from natural DHA, all six methylene skipped cis-configured double bonds were incorporated into the final product, via a stereocontrolled semi-hydrogenation reaction to achieve the n-18 double bond. The synthesis was accomplished with an overall yield of 5.3% over 10 steps as the longest linear sequence, providing reliable access to this elusive polyunsaturated natural product. In addition to the synthetic efforts, the biological relevance of the methoxylated ether lipid was further validated via molecular docking and molecular dynamics simulations with soybean 15-lipoxygenase-1. The simulations predict a moderate binding affinity (Boltz-2 predicted IC50 = 4.6 μM, Glide score = -9.0 kcal mol-1, MM/GBSA ΔGbind = -60 kcal mol-1), comparable to that of arachidonic acid. Finally, a substrate assay with soybean 15-lipoxygenase-1 confirms that the DHA like methoxylated ether lipid is a substrate for the enzyme, displaying 15% relative activity compared to arachidonic acid.

During an infection, prostaglandin E 2 (PGE 2 ) mediates immune responses in insects and later epoxyoctadecamonoenoic acids (EpOMEs) are produced from linoleic acid to suppress excessive and unnecessary immune responses. Intracellular signaling pathway by which these oxylipins suppress the immune responses was previously unclear. This study demonstrated that EpOMEs antagonize the secondary messengers induced by PGE 2 in a lepidopteran species, Maruca vitrata . PGE 2 injections significantly increased hemocyte-spreading behavior, along with raised calcium ion and cAMP levels in hemocytes, and also up-regulated phenoloxidase activity and expressions of antimicrobial peptides. These cellular and humoral immune responses induced by PGE 2 were dose-dependently inhibited by EpOMEs, with 12,13-EpOME being more effective than 9,10-EpOME in immunosuppression. PGE 2 treatment also elevated the total number of circulating hemocytes, with the majority (88.4%) of these increased hemocytes being granulocytes. Conversely, EpOMEs suppressed the up-regulation of total hemocyte count induced by PGE 2 and directly reduced the total hemocyte count by inducing apoptosis in granulocytes, as visualized by the TUNEL assay. These immunosuppressive and cytotoxic effects suggest the potential of EpOME as a lead compound for developing a novel type of insecticides. To chemically stabilize EpOMEs, the epoxide group was replaced with a propoxide group, and the carboxylic terminal was methylated. The 12-propoxyl regioisomer was selected based on immunosuppressive bioassays. Further investigation of the two possible enantiomers of 12-propoxyl regioisomer showed that the 12 R -enantiomer was more effective than the 12 S -enantiomer in immunosuppression. The resulting 12 R -propoxy octadecamonoenoic methyl ester displayed insecticidal activities at low nanogram levels per insect by hemocoelic injection and at < 50 ppm by the leaf-dipping method against three lepidopteran insects.

The hematopoietic stem cell (HSC) niche in the bone marrow (BM) supports HSC function, fate and numbers [1]. Sympathetic fibres innervate the BM and are components of the hematopoietic stem and progenitor cell (HSPC) niche [2]. Neuropathy of the HSPC niche is present and essential for disease development in experimental models of JAK2V617F+ myeloproliferative neoplasms (MPN) and MLL-AF9+ acute myeloid leukemia (AML), and it is present in the BM of human MPN and AML patients [3–6]. Neuropathy contributes to mutant HSC expansion and represents an effective therapeutic target to block disease progression in JAK2V617F+ MPN mice [3]. The sympathomimetic agonist mirabegron restored nestin+ cells and reduced reticulin fibrosis in MPN patients [7]. Here, we show that neuropathy of the HSPC niche emerges in two additional experimental models of hematological disease including pre-leukemic myelopoiesis driven by NRASG12D and lymphoma/lymphoblastic leukemia driven by p53 deletion. Neuropathy involves severe ultrastructural damage in NRASG12D+ mice and AML patients as shown by electron microscopy. When further reinforced chemically, neuropathy has a profound impact on the experimental NRASG12D mouse model, promoting myeloid bias, reducing HSPC numbers and inducing changes in the stem cell microenvironment that include reduced numbers of mesenchymal stromal cells (MSC) and increased presence of morphologically abnormal blood vessels in BM. Together, BM neuropathy is a prevalent factor in hematopoietic malignancies that involves important degradation of sympathetic fibres and contributes to disease in a different manner depending on the driver mutation. This should be taken in consideration in the clinic, given that chemotherapy induces neuropathy of the HSC niche [8] and it is the most frequent first line treatment for AML, acute lymphoblastic leukemia and MPN patients.

Nineteen potential mimics of 8,9-epoxyeicosatrienoic acid (8,9-EET), a natural bioactive oxylipin, were synthesized and evaluated for their ability to protect renal mesangial cells against sorafenib-induced cell death in a water-soluble tetrazolium (WST-8) assay. All compounds were also evaluated as inhibitors of soluble epoxide hydrolase. As expected of a potent pan-kinase inhibitor the drug sorafenib caused a significant decrease in cell viability in HRMCs. Several analogs containing amide and oxamide groups in place of the epoxide showed efficacy in reducing sorafenib induced human renal mesangial cell (HRMC) death. Oxamide containing analogs proved particularly effective, with the most promising analog increasing cell viability five-fold over control at 1 µM. These analogs, containing an oxamide group as a bioisostere for the epoxide in 8,9-EET, did not display significant inhibitory activity towards soluble epoxide hydrolase. This preliminary structure–activity relationship analysis reveals the oxamide group as a promising bioisostere for the epoxide in the 8,9-position of the fatty acid chain, producing protective effects against sorafenib-induced cell death in HRMCs. Collectively, these findings demonstrate the potential for using epoxide mimics and particularly oxamides as 8,9-EET analogs as bioisosteres of the corresponding epoxide in a therapeutic strategy against sorafenib-induced glomerular nephrotoxicity.

Background: This study investigates how sorafenib induces toxicity in glomerular cells and examines the protective role of 8,9-epoxyeicosatrienoic acid (8,9-EET) analogs in reducing this kidney damage. Methods: Human renal mesangial cells (HRMCs) and podocytes were treated with no treatment, sorafenib alone, or sorafenib combined with 8,9-EET analogs. Cell viability and apoptosis were measured in both cell types. Results: Sorafenib (1–10 µM) lowered cell viability and increased caspase 3/7 activity in a dose-dependent way in HRMCs and podocytes. Five of twenty 8,9-EET analogs significantly enhanced cell survival and decreased apoptosis. RNA sequencing showed that sorafenib altered 1244 genes, including those involved in cell cycle and the Raf/MEK/ERK pathway. The 8,9-EET analog MDB-52a raised ANGPTL4 levels, linked to metabolism and vascular health, and reduced ACTA2, which could activate protective pathways. Nephroseq data correlated these gene changes with glomerulosclerosis. Conclusions: MDB-52 appears to counteract gene disruptions and protect against sorafenib-induced kidney damage. Overall, 8,9-EET analogs targeting glomerular cells could be potential therapeutic agents to lessen sorafenib-related nephrotoxicity.

Lipid metabolism is important for alternative (M2) macrophage activation, but it remains unclear whether it is essential for this process, and the underlying mechanisms have yet to be determined. It is also unclear how the M2 phenotype is induced during the resolution of inflammation and tissue repair. We used large-scale RNA-sequencing and high-throughput lipidomics approaches to identify that during blood coagulation, granulocytes release certain lipids that are loaded onto high-density lipoproteins (HDLs), which then act via scavenger receptors SR-B1 and SR-B3 - to mediate the expression of 26 of 32 M2-associated genes and oxidative phosphorylation (OXPHOS) in macrophages. We found that in the absence of these lipids, interleukin-4 (IL-4) induced only 6 of 32 M2 markers, and this cytokine alone failed to induce OXPHOS. We also found that the HDL-associated C18:0, C18:2, and C20:3 fatty acids (FAs) were the lipids that most potently induced the M1-to-M2 transition. Furthermore, we determined that during IL-4-mediated inflammation, the inhibition of blood coagulation, or platelet and granulocyte depletion, results in a substantial decrease in M2 marker expression. Thus, this study identified that granulocyte-derived FAs mediate the reprogramming of macrophages towards the M2 phenotype, thereby bridging the processes of blood coagulation, inflammation, and repair. Highlights ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes

Excessive and unnecessary immune responses cause serious adverse effects due to self-tissue damage and energy consumption, particularly at the late stage of infection to terminate the induced immunity. Unlike mammals, which use long-chain fatty acid oxylipins, C18 oxygenated polyunsaturated fatty acids are suggested to act as immune resolvins in insects, including two epoxyoctadecamonoenoic acids (9,10-EpOME and 12,13-EpOME). This study investigated the physiological roles of EpOMEs in immune resolution in the lepidopteran insect, Maruca vitrata. The levels of two EpOMEs in the larvae increased during the late infection stage upon immune challenge. At their peak concentrations at 96 h post-infection (pi), both EpOMEs were found at similar levels: 323.18 pg/mg body weight for 9,10-EpOME and 322.07 pg/mg body weight for 12,13-EpOME. Both EpOMEs inhibited cellular and humoral immune responses, with 12,13-EpOME being more potent than 9,10-EpOME. Genes associated with EpOME synthase and degradation, identified as Mv-CYP1 and Mv-sEH, were detected in various developmental stages and tissues of M. vitrata. RNA interference (RNAi) targeting Mv-CYP1 failed to inhibit the immune response, whereas RNAi targeting Mv-sEH enhanced the immunosuppression. In contrast to the acute (< 12 h pi) immune response involving eicosanoid biosynthesis, the expression of these two genes linked to EpOME metabolism increased significantly at the late infection stage (> 12 h pi). Several alkoxide analogs of EpOME, with the epoxide group replaced by an alkoxide group, were synthesized; one such derivative demonstrated substantially greater efficacy than the natural EpOMEs in inhibiting the immune response. Additionally, using EpOME alkoxide significantly increased the effectiveness of microbial insecticides. Moreover, exposing young larvae to sublethal doses of EpOME alkoxide or sEH inhibitor induced severe developmental delays. These results suggest a novel strategy for insect pest control using insect immune resolvin analogs.

Research over the last 25 years related to structural elucidations and biological investigations of the specialized pro-resolving mediators has spurred great interest in targeting these endogenous products in total synthesis. These lipid mediators govern the resolution of inflammation as potent and stereoselective agonists toward individual G-protein-coupled receptors, resulting in potent anti-inflammatory activities demonstrated in many human disease models. Specialized pro-resolving mediators are oxygenated polyunsaturated products formed in stereoselective and distinct biosynthetic pathways initiated by various lipoxygenase and cyclooxygenase enzymes. In this review, the reported stereoselective total synthesis and biological activities of the specialized pro-resolving mediators biosynthesized from the polyunsaturated fatty acid n-3 docosapentaenoic acid are presented.

Upon immune challenge, recognition signals trigger insect immunity to remove the pathogens through cellular and humoral responses. Various immune mediators propagate the immune signals to nearby tissues, in which polyunsaturated fatty acid (PUFA) derivatives play crucial roles. However, little was known on how the insects terminate the activated immune responses after pathogen neutralization. Interestingly, C20 PUFA was detected at the early infection stage and later C18 PUFAs were induced in a lepidopteran insect, Spodoptera exigua. This study showed the role of epoxyoctadecamonoenoic acids (EpOMEs) in the immune resolution at the late infection stage to quench the excessive and unnecessary immune responses. In contrast, dihydroxy-octadecamonoenoates (DiHOMEs) were the hydrolyzed and inactive forms of EpOMEs. The hydrolysis is catalyzed by soluble epoxide hydrolase (sEH). Inhibitors specific to sEH mimicked the immunosuppression induced by EpOMEs. Furthermore, the inhibitor treatments significantly enhanced the bacterial virulence of Bacillus thuringiensis against S. exigua. This study proposes a negative control of the immune responses using EpOME/DiHOME in insects.

Abstract ID 94779Poster Board 284Background: Adverse effects related to sorafenib VEGF-TKI inhibitor treatment is one of the biggest challenges in onconephrology. Sorafenib is used to treat late-stage advanced carcinoma that cannot be treated by surgery; however, a significant percentage of patients lose kidney function during or after treatment. Nephrotoxicity is caused by the interaction between VEGF-TKIs and kidney function, which can result in hypertension and glomerular injury leading to proteinuria that has a negative impact on life quality even if therapy is suspended or discontinued. A primary goal of this project is to determine mechanisms responsible for sorafenib glomerular cell toxicity and to test novel epoxylipid based compounds to maintain glomerulus cell integrity.Hypothesis: 8,9 epoxyeicosatrienoic acids (EETs) analogs will prevent or reduce sorafenib-related nephrotoxicity through unique cell signaling mechanisms.Methods: Human renal mesangial cells (HRMCs) were grown at 37°C in RPMI 1640 medium with 10% FBS, 100 U/ml penicillin and 0.1 mg/ml streptomycin. Sorafenib and 8,9-EET analogs were evaluated: untreated cells, cells treated with sorafenib (10 μM), and cells treated sorafenib with varying 8,9-EET analog concentrations (1, 3, and 10 μM). Live cell imaging was conducted to analyze the apoptotic caspase 3/7 activity of the HRMCs every two hours for 48 hours via an Incucyte system. WST assay was used to determine cell viability. An RNA sequencing method was utilized to identify crucial mesangial cell genes linked to sorafenib nephrotoxicity and 8,9-EET protection.Results: In present study we observed the that glomerular mesangial cell viability dose-dependently decreased in response to sorafenib. HMRC viability was 84, 74 and 10% at 1, 3 and 10 μM sorafenib; respectively. Nineteen 8,9 EET analogs were screened for soluble epoxide hydrolase (sEH) inhibitory activity against human sEH recombinant protein and their ability to improve HMRC viability during sorafenib exposure. Six 8,9-EET analogs significantly reduced sorafenib related HRMC cell death as assessed by WST assay. Two 8,9-EET analogs, RM-84 and MBD-32, reduced sorafenib induced HMRC caspase 3/7 activity by 20-40%. Better protective effects were found with the 8,9-EET analogs, MDB-52-I and MDB-52-II, which dose dependently reduced sorafenib induced HMRC caspase 3/7 activity by 60-90%.Next, we evaluated the effect of sorafenib and 8,9-EET analog at the pathway level by carrying out a differential RNA sequencing using MDB-52-I. Comparing no treatment to cells treated with sorafenib, 1244 genes were found to be significantly expressed. The top 50 significantly differentially downregulated HMRC genes were key genes involved in the cell cycle pathway, such as CDC25, E2F2, MCM10, and MYBL2. In contrast, DUSP9 and RRAGD genes involved in the Raf/MEK/ERK pathway were upregulated in HMRC by sorafenib. HRMCs treated with the 8,9-EET analog, MDB-52-II, had increased expression of ANGPTL4 which inhibits lipoprotein lipase activity, a key regulator of metabolism and vascular homeostasis. Comparing sorafenib to sorafenib and MDB-52 I and sorafenib, RP11-178L8.4 displayed more expression in 8,9 EET analog treated which could activate glomerular mesangial cell protective molecular signaling.Summary: The findings of our study demonstrate that 8,9-EET analogs through actions on glomerular mesangial cell signaling pathways could be a therapeutic agent to prevent sorafenib-induced glomerular nephrotoxicity.

Liver sinusoidal endothelial cells (LSECs) are fenestrated endothelial cells with a unique, high endocytic clearance capacity for blood-borne waste macromolecules and colloids. This LSEC scavenger function has been insufficiently characterized in liver disease. The Glmpgt/gt mouse lacks expression of a subunit of the MFSD1/GLMP lysosomal membrane protein transporter complex, is born normal, but soon develops chronic, mild hepatocyte injury, leading to slowly progressing periportal liver fibrosis, and splenomegaly. This study examined how LSEC scavenger function and morphology are affected in the Glmpgt/gt model. FITC-labelled formaldehyde-treated serum albumin (FITC-FSA), a model ligand for LSEC scavenger receptors was administered intravenously into Glmpgt/gt mice, aged 4 months (peak of liver inflammation), 9-10 month, and age-matched Glmpwt/wt mice. Organs were harvested for light and electron microscopy, quantitative image analysis of ligand uptake, collagen accumulation, LSEC ultrastructure, and endocytosis receptor expression (also examined by qPCR and western blot). In both age groups, the Glmpgt/gt mice showed multifocal liver injury and fibrosis. The uptake of FITC-FSA in LSECs was significantly reduced in Glmpgt/gt compared to wild-type mice. Expression of LSEC receptors stabilin-1 (Stab1), and mannose receptor (Mcr1) was almost similar in liver of Glmpgt/gt mice and age-matched controls. At the same time, immunostaining revealed differences in the stabilin-1 expression pattern in sinusoids and accumulation of stabilin-1-positive macrophages in Glmpgt/gt liver. FcγRIIb (Fcgr2b), which mediates LSEC endocytosis of soluble immune complexes was widely and significantly downregulated in Glmpgt/gt liver. Despite increased collagen in space of Disse, LSECs of Glmpgt/gt mice showed well-preserved fenestrae organized in sieve plates but the frequency of holes >400 nm in diameter was increased, especially in areas with hepatocyte damage. In both genotypes, FITC-FSA also distributed to endothelial cells of spleen and bone marrow sinusoids, suggesting that these locations may function as possible compensatory sites of clearance of blood-borne scavenger receptor ligands in liver fibrosis.

Here we explored the role of interleukin-1β (IL-1β) repressor cytokine, IL-1 receptor antagonist (IL-1rn), in both healthy and abnormal hematopoiesis. Low IL-1RN is frequent in acute myeloid leukemia (AML) patients and represents a prognostic marker of reduced survival. Treatments with IL-1RN and the IL-1β monoclonal antibody canakinumab reduce the expansion of leukemic cells, including CD34 + progenitors, in AML xenografts. In vivo deletion of IL-1rn induces hematopoietic stem cell (HSC) differentiation into the myeloid lineage and hampers B cell development via transcriptional activation of myeloid differentiation pathways dependent on NFκB. Low IL-1rn is present in an experimental model of pre-leukemic myelopoiesis, and IL-1rn deletion promotes myeloproliferation, which relies on the bone marrow hematopoietic and stromal compartments. Conversely, IL-1rn protects against pre-leukemic myelopoiesis. Our data reveal that HSC differentiation is controlled by balanced IL-1β/IL-1rn levels under steady-state, and that loss of repression of IL-1β signaling may underlie pre-leukemic lesion and AML progression.

Background: Although many new treatment options have become available, multiple myeloma (MM) is still considered an incurable disease. The importance of achieving minimal residual disease (MRD) negativity in MM patients has become clearer in recent years. Multiple studies show that bone marrow based MRD assessment is one of the strongest prognostic factors, and deeper responses correlate with more favorable outcomes. The REMNANT study will evaluate if treating at MRD relapse after first line (1.L) treatment prolongs progression-free survival (PFS) and overall survival (OS) in MM patients. Methods: The REMNANT study (RElapse from Mrd Negativity As iNdication for Treatment) is an academic, multicenter, open-label, randomized phase 2/3 study of newly diagnosed (ND) MM patients eligible for autologous stem cell transplant (ASCT). The study has a population-based approach with few exclusion criteria, implying that patients with kidney failure, amyloidosis, plasma cell leukemia and other comorbidities are enrolled. To increase enrollment in part 2, patients who have received 1.L treatment outside the REMNANT study can be enrolled directly if they are >CR/MRD negative. 391 NDMM patients (age 18-75 years) eligible for ASCT will be enrolled in part 1 (phase 2) of the study and receive standard of care Norwegian 1.L treatment; 4 pre-transplant induction and 4 post-transplant consolidation cycles of bortezomib, lenalidomide and dexamethasone (VRd). After induction, patients will undergo tandem or single transplant, depending on toxicity and response to first transplant. All patients receive lenalidomide maintenance. Following 1.L treatment 176 patients achieving MRD negative (Euroflow NGF 10 -5) complete response will be enrolled in part 2 (phase 3) of the study. Patients will be randomized in a 1:1 ratio to receive second line treatment (2.L) at MRD relapse in arm A or at PD in arm B. At loss of MRD negativity in arm A or at PD in arm B, 2.L treatment will be daratumumab, carfilzomib and dexamethasone until PD. The primary endpoint of part 1 (phase 2) of the study is the number of patients who achieve MRD negative (Euroflow NGF 10 -5) complete response 30-45 days post consolidation. Secondary endpoints includes response rates, safety evaluations and patient-reported outcome. The co- primary endpoints in part 2 (phase 3) are PSF and OS from randomization to progressive disease or death on 2.L treatment. We will also compare different methods for measuring MRD: NGF Euroflow, Next Generation Sequencing, mass spectrometry and PET-CT. We want to evaluate how the different methods compare when it comes to sensitivity and outcome (PFS and OS). Results: As of July 18 th 2023, 291 patients are enrolled in part 1 and 97 in part 2 (23 directly enrolled). Baseline characteristics, safety summary and preliminary results can be found in Table 1. The ORR on first line treatment is 95% and 65 of 152 patients (45%) were >CR and MRD negative at the post-consolidation visit. Patients achieving > VGPR but not CR MRD negativity post consolidation are followed for up to 24 months on lenalidomide maintenance, and 11 of 74 patients (15%) in follow-up have converted to >CR/MRD negativity at a median time of seven months (range 2-16). Nine patients have started 2.L treatment in part 2 (phase 3), eight in arm A (MRD guided) and one in arm B (control arm). Median time to loss of MRD negativity among the eight patients in arm A was four months (range 1-6). The most common adverse events were infections, occurring in 24% of patients (any grade). During 1.L treatment, 61 patients have left the study. Seven patients have died, 27 discontinued due to disease progression, 12 patients have withdrawn from the study and seven discontinued due to adverse events. 59% of the patients who progressed during 1. L treatment had high-risk cytogenetics (with gain1q and/or del17p and/or t(4;14)). Conclusion: Standard of care Norwegian first line treatment has an ORR of 95%. The MRD negativity rate among patients who have finished 1.L treatment was 43% (65 of 152). The median time to loss of MRD negativity in arm A (MRD guided) was 4 months.

Study objective: Sorafenib an antiangiogenic drug which are widely used in cancer treatment, and it inhibits vascular endothelial growth factor (VEGF) and tyrosine kinases (TK)involved in both tumor cell proliferation and angiogenesis. Unfortunately, VEGF and TK inhibitors cause severe kidney glomerular injury and proteinuria. Kidney injury that occurs with sorafenib chemotherapeutic treatment is a major clinical challenge that lacks a drug to revert or reduce this kidney glomerular cell damage. Hypothesis: Epoxyeicosatrienoic acid (EET) mimics reduce the nephrotoxic effects of sorafenib on glomerular mesangial cells. Methodology: Human renal mesangial cells (HRMCs) were cultured at 37˚C in RPMI 1640 medium containing 10% FBS, 100 U/ml penicillin, and 0.1 mg/ml streptomycin. Live cell imaging was performed to monitor real-time cell death activity in HRMCs. Apoptosis was determined using the caspase 3/7 dye and the HRMCs cells were imaged every 2 hours for 72 hours using the Incucyte system. HMRCs were tested under four conditions: 1) Sorafenib (10 μM), 2) Sorafenib (10 μM) plus 8,9-EET analogs (1 μM), 3) Sorafenib (10 μM) plus 8,9-EET analogs (3 μM), 4) Sorafenib (10 μM) plus 8,9-EET analogs (10 μM). Thirteen 8,9-EET analogs were also tested for soluble epoxide hydrolase (sEH) inhibitory activity against human sEH recombinant protein. Results: Sorafenib caused significant cell death and increased caspase 3/7 activity in HRMCs. Nine of the 8,9-EET analogs were ineffective in reducing sorafenib induced HRMC cell death and caspase 3/7 activity. Four 8,9-EET analogs in a dose-dependent manner reduced sorafenib induced cell death in HRMCs. This preliminary structure activity relationship analysis revealed an oxamide group as a bioisostere for the epoxide in the 8,9-position of the fatty acid chain, producing protective effects against sorafenib induced cell death in HRMCs. Gratifyingly, this group lacked significant sEH-inhibitory activity. The 8,9-EET analogs RM-84 and MBD-32 reduced sorafenib induced caspase 3/7 activity by 20-40% in HRMCs. Additional protective action was found with the 8,9-EET analogs MDB-52-I the MDB-52-II which dose dependently reduced sorafenib induced caspase 3/7 activity by 60-90% in HRMCs. Conclusion: Collectively, these findings demonstrate the potential for 8,9-EET analogs as a therapeutic strategy against sorafenib-induced glomerular nephrotoxicity. Arkansas Research Alliance This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.