Acute Treatment Research Articles

Comparison of the Effects of Gradual and Acute Treatment with Mn on Physiological Responses of Rumex hydrolapathum Plants

An understudied problem in plant heavy metal biology is the effects of acute versus gradual or chronic metal exposure. The aim of the present study was to compare the growth and physiological responses of Rumex hydrolapathum Huds. plants subjected to gradual or acute Mn stress treatment in controlled conditions. Heavy metal was applied to substrate either as one 1.00 g L−1 Mn dose (acute treatment) or the same dose in four steps of increasing amounts within 12 days (gradual treatment). Peroxidase activity in actively photosynthesizing leaves was used for monitoring induced biochemical changes resulting from Mn treatment. The number of leaves per plant significantly increased in the case of gradual treatment with Mn, but this effect was not statistically significant for acute treatment. Leaf fresh mass significantly decreased in both cases due to the decrease in leaf water content, but dry biomass of leaves was not affected, with no significant differences between the two types of treatments. A significantly lower chlorophyll fluorescence parameter Performance Index in large leaves of plants under the acute Mn treatment than in plants under the gradual treatment was evident. An increase in leaf peroxidase activity by Mn treatment was proportional to the metal dose received, but plants in the acute treatment with 1.00 g L−1 Mn had a significantly lower peroxidase response in comparison to the gradual treatment with 1.00 g L−1 Mn. In conclusion, under gradual treatment, biochemical changes related to the induction of tolerance to the heavy metal are expressed, as indicated by the continuous increase in leaf peroxidase activity after each treatment step.

Service delivery in acute ischemic stroke patients: Does sex matter?

Women with acute ischemic stroke (AIS) are older and have greater preexisting handicap than men. Given that these factors do not fully explain their poorer long-term outcomes, we sought to investigate potential sex differences in the delivery of acute stroke care in a large cohort of consecutive AIS patients. We analyzed all patients from ASTRAL (Acute Stroke Registry and Analysis of Lausanne) from March 2003 to December 2019. Multivariable analyses were performed on acute time metrics, revascularization therapies, ancillary examinations for stroke workup, subacute symptomatic carotid artery revascularization, frequency of change in goals of care (palliative care), and length of hospital stay. Of the 5347 analyzed patients, 45% were biologically female and the median age was 74.6 years. After multiple adjustments, female sex was significantly associated with higher onset-to-door (adjusted hazard ratio [aHR] = 1.09, 95% confidence interval [CI] = 1.04-1.14) and door-to-endovascular-puncture intervals (aHR = 1.15, 95% CI = 1.05-1.25). Women underwent numerically fewer diagnostic examinations (adjusted odds ratio [aOR] = 0.94, 95% CI = 0.85-1.04) and fewer subacute carotid revascularizations (aOR = 0.69, 95% CI = 0.33-1.18), and had longer hospital stays (aHR = 1.03, 95% CI = 0.99-1.07), but these differences were not statistically significant. We found no differences in the rates of acute revascularization treatments, or in the frequency of change of goals of treatments. This retrospective analysis of a large, consecutive AIS cohort suggests that female sex is associated with unfavorable pre- and in-hospital time metrics, such as a longer onset-to-door and door-to-endovascular-puncture intervals. Such indicators of less effective stroke care delivery may contribute to the poorer long-term functional outcomes in female patients and require further attention.

History of Developing Acute Promyelocytic Leukemia Treatment and Role of Promyelocytic Leukemia Bodies.

The story of acute promyelocytic leukemia (APL) discovery, physiopathology, and treatment is a unique journey, transforming the most aggressive form of leukemia to the most curable. It followed an empirical route fueled by clinical breakthroughs driving major advances in biochemistry and cell biology, including the discovery of PML nuclear bodies (PML NBs) and their central role in APL physiopathology. Beyond APL, PML NBs have emerged as key players in a wide variety of biological functions, including tumor-suppression and SUMO-initiated protein degradation, underscoring their broad importance. The APL story is an example of how clinical observations led to the incremental development of the first targeted leukemia therapy. The understanding of APL pathogenesis and the basis for cure now opens new insights in the treatment of other diseases, especially other acute myeloid leukemias.

Cost-effectiveness of severe acute malnutrition treatment delivered by community health workers in the district of Mayahi, Niger

BackgroundA non-randomized controlled trial, conducted from June 2018 to March 2019 in two rural communes in the health district of Mayahi in Niger, showed that including community health workers (CHWs) in the treatment of severe acute malnutrition (SAM) resulted in a better recovery rate (77.2% vs. 72.1%) compared with the standard treatment provided solely at the health centers. The present study aims to assess the cost and cost-effectiveness of the CHWs led treatment of uncomplicated SAM in children 6–59 months compared to the standard national protocol.MethodsTo account for all relevant costs, the cost analysis included activity-based costing and bottom-up approaches from a societal perspective and on a within-trial time horizon. The cost-effectiveness analysis was conducted through a decision analysis network built with OpenMarkov and evaluated under two approaches: (1) with recovery rate and cost per child admitted for treatment as measures of effectiveness and cost, respectively; and (2) assessing the total number of children recovered and the total cost incurred. In addition, a multivariate probabilistic sensitivity analysis was carried out to evaluate the effect of uncertainty around the base case input data.ResultsFor the base case data, the average cost per child recovered was 116.52 USD in the standard treatment and 107.22 USD in the CHWs-led treatment. Based on the first approach, the CHWs-led treatment was more cost-effective than the standard treatment with an average cost per child admitted for treatment of 82.81 USD vs. 84.01 USD. Based on the second approach, the incremental cost-effectiveness ratio of the transition from the standard to the CHWs-led treatment amounted to 98.01 USD per additional SAM case recovered.ConclusionsIn the district of Mayahi in Niger, the CHWs-led SAM treatment was found to be cost-effective when compared to the standard protocol and provided additional advantages such as the reduction of costs for households.Trial registration: ISRCTN with ID 31143316. https://doi.org/10.1186/ISRCTN31143316

Chronic Opioid Treatment Arrests Neurodevelopment and Alters Synaptic Activity in Human Midbrain Organoids.

Understanding the impact of long-term opioid exposure on the embryonic brain is critical due to the surging number of pregnant mothers with opioid dependency. However, this has been limited by human brain inaccessibility and cross-species differences in animal models. Here, a human midbrain model is established that uses hiPSC-derived midbrain organoids to assess cell-type-specific responses to acute and chronic fentanyl treatment and fentanyl withdrawal. Single-cell mRNA sequencing of 25,510 cells from organoids in different treatment groups reveals that chronic fentanyl treatment arrests neuronal subtype specification during early midbrain development and alters synaptic activity and neuron projection. In contrast, acute fentanyl treatment increases dopamine release but does not significantly alter gene expression related to cell lineage development. These results provide the first examination of the effects of opioid exposure on human midbrain development at the single-cell level.

In situ neutrophil apoptosis and macrophage efferocytosis mediated by Glycyrrhiza protein nanoparticles for acute inflammation therapy

In the progression of acute inflammation, the activation and recruitment of macrophages and neutrophils are mutually reinforcing, leading to amplified inflammatory response and severe tissue damage. Therefore, to regulate the axis of neutrophils and macrophages is essential to avoid tissue damage induced from acute inflammatory. Apoptotic neutrophils can regulate the anti-inflammatory activity of macrophages through the efferocytosis. The strategy of in situ targeting and inducing neutrophil apoptosis has the potential to modulate macrophage activity and transfer anti-inflammatory drugs. Herein, a natural glycyrrhiza protein nanoparticle loaded with dexamethasone (Dex@GNPs) was constructed, which could simultaneously regulate neutrophil and macrophage function during acute inflammation treatment by combining in situ neutrophil apoptosis and macrophage efferocytosis. Dex@GNPs can be rapidly and selectively internalized by neutrophils and subsequently induce neutrophils apoptosis through a ROS-dependent mechanism. The efferocytosis of apoptotic neutrophils not only promoted the polarization of macrophages into anti-inflammatory state, but also facilitated the transfer of Dex@GNPs to macrophages. This enabled dexamethasone to further modulate macrophage function. In mouse models of acute respiratory distress syndrome and sepsis, Dex@GNPs significantly ameliorated the disordered immune microenvironment and alleviated tissue injury. This study presents a novel strategy for drug delivery and inflammation regulation to effectively treat acute inflammatory diseases.

A case report of an atypical severe case of skin picking disorder managed by a multidisciplinary team

BackgroundWhile skin picking disorder remains relatively common, it often does not present to psychiatry until significant morbidity or comorbidities are reached. It is described as recurrent picking of skin leading to skin lesions, with repeated attempts to decrease or stop skin picking. It is also often associated with significant distress or functional impairment. There has been limited research in this specific disorder and treatment efficacy has often been poor in severe cases. For various reasons, only a small amount of patients with this disorder present to care, and often to a multidisciplinary team prior to psychiatry.Case presentationThis is a case presentation of a 44 year old male with a complex past psychiatric history, ultimately untreated for an underlying skin picking disorder. He presented for urgent medical care following a self-inflicted wound through the central frontal bone and dura over the course of 2 years. He was treated with current psychiatric evidence based medicine, including an SSRI, antipsychotic augmentation and NAC, along with habit reversal techniques during the admission. He was concurrently managed with the neurosurgery team, initially with a poor prognosis due to the severity of his presentation. He required debriding of the devitalized bone within the adjacent brain to cover the dural defect, IV antibiotics for 6 weeks, and an initial skin graft on his initial admission.ConclusionsThis case in particular highlighted the importance of urgent treatment via a multidisciplinary approach to avoid mortality. It highlights the importance of increasing awareness about the disorder and that treatment with SSRI’s, along with antipsychotic and NAC adjuncts remains the mainstay of acute treatment.

Acute treatment of migraine: quantifying the unmet need through real-world data in Italy.

This study is describing subjects with migraine interrupting or not receiving triptans for acute treatment and providing a national-level estimate of people who might benefit from different therapeutic approaches. This is a retrospective analysis using IQVIA Longitudinal Patient Database. Starting from 18 + years old individuals with migraine, we selected two cohorts: subjects with triptans prescriptions before and no triptans prescriptions after Index Date (triptan withdraw) and subjects without triptans prescriptions both before and after Index Date (no triptan prescriptions). Index Date was the first record of a health encounter for migraine in 2019. Individuals with cardiovascular disease (CVD) within no triptan prescriptions group were also quantified. Triptan withdraw and no triptan prescriptions cohorts numbered 605 and 3270, respectively, 5% and 29% of subjects with migraine. Mean age was 47 and 51years respectively; women were more represented (~ 80%). Hypertension and thyroid disease were most frequent comorbidities; non-steroidal anti-inflammatory drugs were among most frequently recorded treatments. Subjects with CVD within no triptan prescriptions cohort were 621 and with triptan withdraw cohort subjects represented the basis to estimate those who might benefit from alternative options for the acute treatment of migraine, who were around 60,000 and accounted for 11% of subjects seeking primary care due to migraine. This analysis provides a real-word estimate of Italian people that might benefit from different therapeutic approaches as an alternative to triptans, which sometimes might be not effective and/or poorly tolerated. Such estimate should be intended as the lower limit of a wider range due to strict criteria adopted.

Effects of Prior Metformin Use on Stroke Outcomes in Diabetes Patients with Acute Ischemic Stroke Receiving Endovascular Treatment.

Diabetes mellitus (DM) predisposes individuals to vascular injury, leading to poor outcomes after ischemic stroke and symptomatic hemorrhagic transformation (SHT) after thrombolytic and endovascular treatment (EVT). Metformin (MET), an oral antidiabetic drug, has shown potential neuroprotective effects, but its impact on stroke prognosis in DM patients undergoing EVT remains unclear. In a multicenter study, 231 patients with DM undergoing EVT for acute ischemic stroke were enrolled. Prior MET use was identified, and patients were stratified into MET+ and MET- groups. Demographics, clinical data, and outcomes were compared between groups. Multivariate analysis was used to assess the effect of MET on stroke prognosis. Of the enrolled patients, 59.3% were previously on MET. MET+ patients had lower initial infarct volumes and NIHSS scores compared to MET-taking patients. Multivariate analysis showed that MET+ was associated with a lower risk of stroke progression and SHT (with stroke progression as follows: odd ratio [OR] 0.24, 95% confidence interval [CI] [0.12-0.48], p < 0.001; SHT: OR 0.33, 95% CI [0.14-0.75], p = 0.01) and was also associated with better 3-month functional outcomes (mRS 0-2) after EVT. Prestroke MET use in DM patients undergoing EVT is associated with improved stroke prognosis, including reduced risk of stroke progression and SHT and better functional outcomes. These findings suggest the potential neuroprotective role of MET in this population and highlight its clinical utility as an adjunctive therapy in the management of ischemic stroke. Further research is warranted to elucidate the underlying mechanisms and to optimize MET therapy in this setting.

Computed Tomography to Exclude Cardiac Thrombus in Atrial Fibrillation-An 11-Year Experience from an Academic Emergency Department.

Computed tomography (CT) could be a suitable method for acute exclusion of left atrial appendage thrombus (LAAT) prior to cardioversion of atrial fibrillation (AF) and atrial flutter (AFL) at the emergency department. Our aim was to present our experiences with this modality in recent years. This registry-based observational study was performed at the Department of Emergency Medicine at the Medical University of Vienna, Austria. We studied all consecutive patients with AF and AFL who underwent CT between January 2012 and January 2023 to rule out LAAT before cardioversion to sinus rhythm was attempted. Follow-ups were conducted by telephone and electronic medical records. The main variables of interest were the rate of LAAT and ischemic stroke at follow-up. A total of 234 patients (143 [61%] men; median age 68 years [IQR 57-76], median CHA2DS2-VASc 2 [IQR 1-4]) were analyzed. Follow-up was completed in 216 (92%) patients after a median of 506 (IQR 159-1391) days. LAAT was detected in eight patients (3%). A total of 163 patients (72%) in whom LAAT was excluded by CT were eventually successfully cardioverted to sinus rhythm. No adverse events occurred during their ED stay. All patients received anticoagulation according to the CHA2DS2-VASc risk stratification, and no patient had suffered an ischemic stroke at follow-up, resulting in an incidence risk of ischemic strokes of 0% (95% CI 0.0-1.2%). LAAT was rare in patients admitted to the ED with AF and AFL who underwent cardiac CT prior to attempted cardioversion. At follow-up, no patient had suffered an ischemic stroke. Prospective studies need to show whether this strategy is suitable for the acute treatment of symptomatic AF in the emergency setting.

History and prospects for the use of morphine in clinical practice: literature review

The authors analyzed various studies on acute and chronic pain syndrome treatment. This review provides brief historical data on the discovery and use of morphine from ancient times to present. Morphine remains one of the most common painkillers worldwide and has a rich history dating back more than 200 years. Its basic properties, pharmacokinetics, pharmacodynamics, and principles of use are discussed. No drug has had such an impact on society as morphine because of its medical use as a pain reliever and its illicit use as a drug of addiction and abuse. This review includes the main modern recommendations for the treatment of acute and chronic pain, particularly from the World Health Organization for the treatment of chronic pain and the Procedure-Specific Postoperative Pain Management (PROSPECT) group for the treatment of postoperative pain in various surgical interventions. The types of opioids and their clinical use are described, and the authors’ opinion on the current use of morphine for treating acute and chronic pain syndrome is presented.

Long-term treatment with lasmiditan in patients with migraine: post hoc analysis of treatment patterns and outcomes from the open-label extension of the CENTURION randomized trial

BackgroundThe objective of this analysis was to gain new insights into the patient characteristics and other factors associated with lasmiditan usage and clinical outcomes under conditions resembling the real-world setting.MethodsThis was a post hoc analysis of data from the 12-month, open-label extension (OLE) of the phase 3, double-blind, randomized, controlled CENTURION trial, which examined the efficacy and safety of lasmiditan as acute treatment across four migraine attacks. Patients completing the main study who treated ≥ 3 attacks could continue in the OLE. The initial lasmiditan dose was 100 mg, with dose adjustments to 50 mg or 200 mg allowed at the investigator’s discretion. Patient and clinical characteristics were summarized by dosing pattern and completion status. Safety was assessed based on adverse event (AE) frequency by number of doses.ResultsIn total, 445 patients treated ≥ 1 migraine attacks with lasmiditan during the OLE, 321 of whom (72.1%) completed the study. Forty-seven percent of patients remained on the 100-mg initial dose during the OLE whereas 20.2% used both 100 mg and 50 mg, 30.6% used both 100 mg and 200 mg, and 6 (1.3%) used multiple dose levels. All dosing patterns were associated with clinical and patient-reported improvement; however, the 100-mg group had the highest proportion of patients reporting improvement in the Patient Global Impression of Change – Migraine Headache Condition (56.5% vs 33.4%–52.2%). In comparison, all three groups that made dose adjustments had higher rates of completion compared to the 100-mg group (72.1%–83.3% vs 68.9%). The frequency of AEs decreased with continued use of lasmiditan. Concomitant triptans and lasmiditan use did not increase AE frequency.ConclusionsBased on high persistence and patient satisfaction rates, the 100-mg dose appears optimal for most patients. For those who adjusted dose levels, dose adjustments appeared beneficial to improve efficacy or tolerability, retaining patients on treatment. Collectively, the data suggest that patients who experienced efficacy continued to use lasmiditan regardless of the occurrence or frequency of AEs, and continued use appeared associated with fewer AEs.Trial registrationEuropean Union Drug Regulating Authorities Clinical Trials Database (EudraCT): 2018–001661-17; ClinicalTrials.gov: NCT03670810; registration date: September 12, 2018.Graphical

Effects of acute and chronic methylphenidate on prepulse inhibition: A sex difference study in Wistar rats

BackgroundThe utilization of methylphenidate (MPH) is experiencing a notable surge within the adult population. This growth can be attributed to two key factors: its recreational and cognitive enhancement purposes, as well as the rising prevalence of ADHD diagnoses within this population. This study examined acute and chronic oral MPH effects on attention in male and female Wistar rats. To this end, we used a prepulse inhibition (PPI) task, which is widely used to assess psychoactive drug effects in both humans and rodents. This task allowed us to evaluate changes in attention by analyzing sensorimotor gating associated with stimulus selection process. MethodsAnimals were administered a clinically relevant dose of MPH (5 mg/kg) daily for seven days. The estrous cycle phases of the female rats were measured during behavioral sessions. The PPI task was conducted 20 min after drug administration on day 1 (acute), day 7 (chronic), and 48 h post-treatment. ResultsResults indicated that both acute and chronic MPH treatment impaired PPI expression in male rats, but not in female rats, regardless of their estrous cycle phase. Furthermore, a differential effect of chronic MPH treatment on the PPI task was found in male rats. Specifically, on the seventh treatment day, the PPI effect was observed when animals undertook the PPI task for the first time but was impaired in those animals in which the initial PPI session occurred under the acute influence of the drug (day 1). ConclusionsThese findings suggest that the impact of MPH on sensorimotor gating responses may vary based on sex and task experience, possibly leading to state-dependent effects in healthy individuals.

Abstract 479: Enhanced payload delivery for acute myeloid leukemia treatment through CD37-targeting DNA nanobots

Abstract Acute Myeloid Leukemia (AML) treatment faces considerable challenges, in particular the delivery of therapeutics with sufficient potency and specificity. Traditional Antibody-Drug Conjugates (ADCs) offer a strategic approach to cancer therapy by combining the targeting capabilities of monoclonal antibodies with the cell-killing effect of cytotoxic drugs. However, the limitations in drug-to-antibody ratio (DAR) and the challenges in controlling the release kinetics have often hindered their therapeutic window suggesting novel approaches are necessary. Our approach integrates DNA nanobot technology to facilitate targeted delivery of anthracycline agents directly to CD37-expressing leukemic cells. CD37, a tetraspanin superfamily antigen, has shown promise as a target for AML due to its selective expression on immune cells and favorable internalization properties. By harnessing DNA origami assembly techniques, we developed a customizable platform capable of accommodating a significantly higher payload of chemotherapeutic agents than traditional ADCs. This increased payload potential, paired with the precision targeting of CD37, presents a potent therapeutic strategy with the possibility of reduced systemic toxicity. Here we present preclinical evidence demonstrating targeted delivery of our DNA nanobot drug delivery device and anthracycline payload to CD37+ AML target cells in vitro. In addition, we show targeted efficacy in vitro and in vivo of our anthracycline-loaded DNA nanobot-enabled delivery system, which significantly outperformed free anthracycline in AML target cells. Collectively, our findings suggest an improvement in the therapeutic index of anthracycline and antimitotic agents as well as the ability to combine multiple drug pathways in a single delivery device. The implications of this work extend beyond AML, offering a versatile platform that could revolutionize ADC chemistry and targeted drug delivery. We propose that our DNA nanobot delivery system signifies a pivotal advancement in the field of targeted cancer therapy, with the potential to overcome longstanding barriers in the treatment of AML and potentially other malignancies. Citation Format: Nicholas Vantangoli, Patrick D. Halley, Jeffrey R. Spitzner, John C. Byrd, Karilyn T. Larkin, Carlos E. Castro, Christopher R. Lucas. Enhanced payload delivery for acute myeloid leukemia treatment through CD37-targeting DNA nanobots [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 479.

Abstract 5321: Chronic use of tobacco products promotes breast cancer progression through α7 nAChR/STING pathway activation

Abstract Tobacco-use is associated with an increased risk of developing aggressive breast cancer, however the cause remains unclear. While there is a dose-dependent decrease of patients’ overall survival due to tobacco-use, the risk persists even after cessation. Here we show that chronic treatment with of breast cancer cells with low-dose nicotine significantly increases tumorsphere formation, self-renewal and tumor growth, while the acute treatment has little effect. Interestingly, these outcomes were noted even weeks after nicotine treatment was stopped. Mechanistically, this was attributed to α7 nAChR, previously described as an essential regulator of inflammation. In fact, α7 nAChR knock-out prevented activation of the STING antiviral pathway by reducing the nicotine-induced mRNA expression of STING, CCL5, CXCL10 and STAT3. Overall, these findings highlight long-term impact of nicotine on cancer progression through α7 nAChR/STING pathway. This may inform new biomarkers for diagnosis and potential new treatment strategies to combat tobacco-related breast cancers. Citation Format: Samson Mugisha, Shahnawaz Baba, Shreyas Labhsetwar, Richard Klemke, Jay Desgrosellier. Chronic use of tobacco products promotes breast cancer progression through α7 nAChR/STING pathway activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5321.

Metformin Use in Type 2 Diabetics and Delirium After Noncardiac Surgery: A Retrospective Cohort Analysis.

The cause of postoperative delirium is unknown, but it is thought to result at least in part from inflammation. Metformin, besides its hypoglycemic properties, demonstrates anti-inflammatory effects systemically and in the brain. We tested the primary hypothesis that chronic metformin use in adults with type 2 diabetes is associated with less delirium during the first 5 days after major noncardiac surgery. Secondary outcomes were a composite of serious complications (myocardial infarction, cardiac arrest, stage 2-3 acute kidney injury [AKI], and mortality) and time to discharge alive. We considered adults with type 2 diabetes who did or did not routinely use metformin daily and had noncardiac surgery. Delirium was assessed by Confusion Assessment Method for Intensive Care Unit (CAM-ICU) or brief Confusion Assessment Method (bCAM) for 5 postoperative days. Postoperative AKI was defined by Kidney Disease Improving Global Guidelines. Logistic regression and generalized estimating equation models accounted for within-patient correlation across multiple surgeries and explored the association between metformin use and postoperative delirium and complications. Inverse propensity score weighting and propensity score calibration (PSC) adjusted for confounding variables. No significant difference was observed in the incidence of postoperative delirium between the 2 groups, with 260 of 4744 cases (5.5%) among metformin users and 502 of 5918 cases (8.5%) cases in nonmetformin users, for an odds ratio of 0.88 (95% confidence interval [CI], 0.73-1.05; P = .155), number-needed-to-expose = 118 patients. Similarly, there were fewer composite complications in metformin users (3.3%) than in nonusers (11.7%); However, the common-effect odds ratio of 0.67 was not statistically significant (97.5% CI, 0.39-1.17; P = .106). Discharge from the hospital was significantly faster in patients who took metformin (3 [interquartile range, IQR, 1-5] days for metformin users and 3 [IQR, 2-6] days for nonmetformin users), with a hazard ratio of 1.07 for early discharge, and tight CIs (1.01-1.13). Chronic metformin use was associated with slightly and nonsignificantly less delirium. However, patients who used metformin had clinically meaningfully fewer major complications, mostly stage 2 to 3 kidney injury. While not statistically significant, the reduction was substantial and warrants further investigation because there is currently no effective preventive measure for perioperative renal injury. Benefit would be especially meaningful if it could be produced by acute perioperative treatment. Finally, metformin was associated with faster hospital discharge, although not by a clinically meaningful amount.

M2-type macrophage membrane-mediated delivery of Carvedilol nanocomplex for acute liver failure treatment and remodeling inflammatory microenvironment

M2-type macrophage membrane-mediated delivery of Carvedilol nanocomplex for acute liver failure treatment and remodeling inflammatory microenvironment

Abstract 5259: Mechanistic evaluations of the immunological and cell biological effects that distinguish eribulin from other microtubule-targeted chemotherapeutics

Abstract Microtubule-targeted agents (MTAs) are some of the most widely used and effective chemotherapeutics and they continue to find utility as the payloads of antibody-drug conjugates and in combination with targeted agents to improve response, including with immune checkpoint inhibitors. While all MTAs have shared antiproliferative effects, over the last decade it has become increasingly clear that individual drugs of this class have distinct effects on microtubule-dependent signaling and trafficking that are critical for their anticancer efficacy. We and others have demonstrated that eribulin is unique from other MTAs in its ability to promote vascular remodeling, reverse epithelial-to-mesenchymal transition (EMT), and increase immune infiltration into tumors both in animal models and in the clinic. However, the mechanism linking eribulin-mediated microtubule destabilization to these phenotypes, which are associated with improved overall survival of eribulin-treated patients, is unclear. We found that acute eribulin treatment at clinically relevant concentrations promotes the production of antitumor cytokines in both immune and cancer cells and synergizes with direct STING agonists to promote enhanced immune infiltration and improved antitumor efficacy in vivo in both breast and bladder cancer models. This effect was shown to involve activation of natural killer cells and is associated with TBK1-mediated IRF3 phosphorylation, which is regulated downstream of the microtubule associated GTPase GEF-H1. Intriguingly, GEF-H1 release from destabilized microtubules has also been shown to enhance the formation of focal adhesions and promote the differentiation of mesenchymal cells to a more epithelial phenotype. We show that eribulin is indeed sufficient to promote the formation and activation of focal adhesion complexes in mesenchymal triple-negative breast cancer cells, which was not observed when cells were subjected to treatment with microtubule stabilizing chemotherapeutics. Both genetic and pharmacological inhibitors of GEF-H1 were utilized to interrogate the relationship between eribulin-mediated microtubule destabilization and TBK1/IRF3-dependent immunological activation as well as the formation of RhoA-dependent focal adhesions and reversal of EMT-associated phenotypes. Together, our data provide a mechanistic rationale for unique effects of eribulin as compared to other classes of MTAs that could inform on the use of these widely used, but mechanistically underappreciated drugs in a more personalized manner and inform on their rational combination with targeted agents, including immunotherapy. Citation Format: Zaineb Hassouneh, Nancy Wilkinson, Leila Takahashi-Ruiz, Neelam Mukherjee, April L. Risinger. Mechanistic evaluations of the immunological and cell biological effects that distinguish eribulin from other microtubule-targeted chemotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5259.

Abstract 4605: AZD4573 in combination with CHOP increases combination benefit in preclinical peripheral T-cell lymphoma models

Abstract Peripheral T-cell Lymphoma (pTCL) makes up about 10% of non-Hodgkin's lymphoma in the United States. Patients with relapsed/refractory pTCL have limited treatment options and poor prognosis. Current standard of care for pTCL revolves around the chemotherapy regimens CHOP/E. Here we examine the efficacy of CDK9 inhibition for the treatment of pTCL. CDK9 regulates transcription through phosphorylation of RNA polymerase II. AZD4573 is a highly potent and selective CDK9 inhibitor; acute inhibition with AZD4573 downregulates short-lived proteins such as MCL-1, BFL-1, and c-MYC, which are often overexpressed in hematologic tumors. It has been shown that the expression pattern of the anti-apoptotic BCL-2 family members in pTCL cell line models closely resembled the expression patterns in pTCL patient samples (Koch et al. 2019). Expression of BCL-2 family members is highly heterogeneous in pTCL, with MCL-1 being the most universally expressed. Using MCL-1 inhibitor AZD5991, we showed statistically significant benefit in survival when combined with CHOP in MCL-1 dependent preclinical pTCL PDX models (Koch et al. 2019). In addition, we have previously reported the importance of the anti-apoptotic protein BFL-1 in cell survival in NHL, including a subset of pTCL (Boiko et al 2021). AZD4573 treatment showed a range of activity across the panel of 18 human pTCL cell lines, in a 6-hour caspase-3/7 activation assay. 14 of the cell lines were sensitive, with EC50 values less than 100 nM, and 13 reached a max caspase activation of over 40%. pTCL subtypes that responded to AZD4573 treatment included ALCL, NK-TCL, and PTCL-NOS and CTCL. Acute AZD4573 treatment resulted in decreased pSer2-RNAP2 and reduced protein levels of c-MYC and MCL-1. To determine what was driving the apoptotic phenotype, we used ribonucleoprotein (RNP) mediated CRISPR knock out (KO) of MYC and MCL1 genes. While pTCL cell lines were dependent on c-MYC and MCL-1 for viability after KO, only MCL-1 KO impaired AZD4573 treatment, suggesting that efficacy is mediated through MCL-1 in ALCL pTCL cell lines assessed. To determine if combining AZD4573 with CHOP improved efficacy, we tested 5 pTCL cell lines in a 6x6 combination dosing matrix and measured viability after 24-72 hours using RealTime-Glo after 24hr exposure to CHOP with AZD4573 added for the last 6hrs. Adding AZD4573 to CHOP in vitro increased the efficacy in pTCL ALCL cell lines with MCL-1 dependency, but not in CTCL cell line with BCL-xL dependency and resistance to AZD4573. CHOP treatment in vitro resulted in a decrease in c-MYC levels but not MCL-1, suggesting that combination benefit may be driven through c-MYC. This data suggests that treatment with AZD4573 as a monotherapy or in combination with CHOP regimen would be an effective therapeutic strategy in pTCL. Citation Format: Danielle Sinead Potter, India Ott, Jamal Saeh, Richard Olsson, Stephen Fawell, Lisa Drew, Justine Roderick. AZD4573 in combination with CHOP increases combination benefit in preclinical peripheral T-cell lymphoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4605.

Abstract 3222: Acute and long-term responses to treatment with the HDAC inhibitor quisinostat in preclinical models of glioblastoma

Abstract Introduction: High expression of histone deacetylases (HDACs), particularly HDAC1, is strongly associated with poor prognosis for glioblastoma (GBM) patients. Quisinostat is a second-generation, class I-II selective HDAC inhibitor with high specificity for HDAC1 and potent anti-tumor activity. Here, we evaluated GBM PDX tissues and glioma stem cells (GSCs) for cellular, transcriptomic and phenotypic changes after acute and long-term treatment with quisinostat. Methods: Multiple GBM PDX models and PDX-derived GSCs were treated with quisinostat, radiation, or a combination of quisinostat and radiation. Tissue and cells were processed for RNA-seq, qRT-PCR, and immunofluorescence assays to examine alterations in neuronal signaling, cell fate, DNA damage, and markers of stemness and differentiation. Results: Bulk RNA sequencing of tumor tissue revealed that chronic co-treatment with quisinostat and radiation led to increased cellular expression of neuronal signaling and neuronal development pathways compared to the untreated control group. Increase in expression of neuronal signaling genes was also observed upon in vitro treatment of GSCs with quisinostat. Immunocytochemistry and immunofluorescence staining confirmed changes in neuronal signaling and neuronal cell fate proteins after quisinostat treatment. Conclusions: Quisinostat treatment induces a shift in tumor cells towards a neuronal-like cell fate. Considering that GSCs have been shown to establish synaptic junctions with healthy neurons to evoke enhanced excitatory currents within glioma cells and contribute to treatment resistance, further investigation of this shift upon HDAC inhibition is crucial. Ongoing studies are aimed at evaluating the significance of these cellular and molecular changes resulting from quisinostat treatment and whether the quisinostat-induced cell fate changes can be exploited for future combination therapy for GBM. Citation Format: Keely Orndorff, James McNamara, Mariya Stavnichuk, Costanza Lo Cascio, Connor White, Ernesto Luna Melendez, Gozde Uzunalli, Nader Sanai, Shwetal Mehta. Acute and long-term responses to treatment with the HDAC inhibitor quisinostat in preclinical models of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3222.