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Translocations of Meningioma-1 (MN1) occur in a subset of acute myeloid leukemias (AML) and result in high expression of MN1, either as a full-length protein, or as a fusion protein that includes most of the N-terminus of MN1. High levels of MN1 correlate with poor prognosis. When overexpressed in murine hematopoietic progenitors, MN1 causes an aggressive AML characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2A -rearranged ( KMT2A -r) leukemia, including high levels of Hoxa and Meis1 gene expression. Compounds that target a critical KMT2A–Menin interaction have proven effective in KMT2A -r leukemia. Here, we demonstrate that Menin ( Men1 ) is also critical for the self-renewal of MN1-driven AML through the maintenance of a distinct gene expression program. Genetic inactivation of Men1 led to a decrease in the number of functional leukemia-initiating cells. Pharmacologic inhibition of the KMT2A–Menin interaction decreased colony-forming activity, induced differentiation programs in MN1-driven murine leukemia and decreased leukemic burden in a human AML xenograft carrying an MN1-ETV6 translocation. Collectively, these results nominate Menin inhibition as a promising therapeutic strategy in MN1-driven leukemia.

Inhibitors of the Menin-KMT2A interaction are promising agents for the treatment of KMT2A-rearranged (KMT2A-r) leukemias. We evaluated Menin inhibition in patient derived xenografts of KMT2A-r leukemias with high-risk features. Three AMLs with high-risk fusion partners (MLLT10, MLLT4) and two infant ALL samples were sensitive to Menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated KMT2A-AFF1 ALL samples were much less sensitive compared to cells obtained earlier in the same patients’ disease course. Since none of the patients had been treated with a Menin inhibitor, resistance in these highly pretreated samples was acquired in the absence to Menin inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy towards the canonical targets in the Menin-inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple co-mutations, including RAS pathway and TP53 mutations, although neither was sufficient to induce Menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patients; inactivation of KMT2C/D had previously been reported to result in Menin inhibitor resistance. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data supports using Menin-inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred.

Inhibitors of the Menin-KMT2A interaction are promising agents for the treatment of KMT2A-rearranged (KMT2A-r) leukemias. We evaluated Menin inhibition in patient derived xenografts of KMT2A-r leukemias with high-risk features. Three AMLs with high-risk fusion partners (MLLT10, MLLT4) and two infant ALL samples were sensitive to Menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated KMT2A-AFF1 ALL samples were much less sensitive compared to cells obtained earlier in the same patients disease course. Since none of the patients had been treated with a Menin inhibitor, resistance in these highly pretreated samples was acquired in the absence to Menin inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy towards the canonical targets in the Menin-inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple co-mutations, including RAS pathway and TP53 mutations, although neither was sufficient to induce Menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patients; inactivation of KMT2C/D had previously been reported to result in Menin inhibitor resistance. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data supports using Menin-inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred.Competing Interest StatementGMM is an employee and shareholder of Syndax Pharmaceuticals Inc. KMB has previously consulted for Agios and Novartis and has received research funding from Syndax Pharmaceuticals Inc. CL received a research training grant from Institut Servier. SKT has served on scientific advisory boards for Kura Oncology and Syndax Pharmaceuticals for pediatric clinical development of Menin inhibitors and receives research funding from Kura Oncology. She also serves on the scientific advisory board for Aleta Biotherapeutics, receives research funding from Beam Therapeutics and Incyte Corporation, received travel support from Amgen, and has consulted for bluebird bio for unrelated studies. MPC has been involved as a consultant for Janssen Pharmaceuticals and on advisory committee for Cartogrpahy Biosciences.Footnotes* Additional experiments were conducted in NSG mice.

Inhibition of the histone methyl-transferase DOT1L (KMT4) has shown encouraging activity in preclinical models of KMT2A (MLL)-rearranged leukemia. The DOT1L inhibitor pinometostat (EPZ5676) was well tolerated in early phase clinical trials and showed modest clinical activity, including occasional complete responses (CRs) as single agent. These studies support the development of combinatorial therapies for KMT2A-rearranged leukemias. Here, we investigated two novel combinations: dual inhibition of the histone methyltransferases DOT1L and EZH2, and the combination of a DOT1L inhibitor with the protein synthesis inhibitor homoharringtonine (HHR). EZH2 is the catalytic histone methyltransferase in the polycomb repressive complex 2 (PRC2), and inhibition of EZH2 has reported preclinical activity in KMT2A-rearranged leukemia. We found that the H3K79 and H3K27 methyl marks are not dependent on each other, and that DOT1L and EZH2 inhibition affect largely distinct gene expression programs. In particular, the KMT2A/DOT1L target HOXA9, which is commonly de-repressed as a consequence of PRC2 loss or inhibition in other contexts, was not re-activated upon dual DOT1L/EZH2 knockout or inhibition. Despite encouraging data in murine KMT2A-MLLT3 transformed cells suggesting synergy between DOT1L and EZH2 inhibition, we found both synergistic and antagonistic effects on a panel of human KMT2A rearranged cell lines. Combinatorial inhibition of DOT1L and EZH2 is thus not a promising strategy. We identified opposing effects on ribosomal gene transcription and protein translation by DOT1L and EZH2 as a mechanism that is partially responsible for observed antagonistic effects. The effects of DOT1L inhibition on ribosomal gene expression prompted us to evaluate the combination of EPZ5676 with a protein translation inhibitor. EPZ5676 was synergistic with the protein translation inhibitor homoharringtonine (HHR), supporting further preclinical/clinical development of this combination. Footnotes * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE134369

Human embryonic stem cell (hESC) progenies hold great promise as surrogates for human primary cells, particularly if the latter are not available as in the case of cardiomyocytes. However, high content experimental platforms are lacking that allow the function of hESC-derived cardiomyocytes to be studied under relatively physiological and standardized conditions. Here we describe a simple and robust protocol for the generation of fibrin-based human engineered heart tissue (hEHT) in a 24-well format using an unselected population of differentiated human embryonic stem cells containing 30-40% α-actinin-positive cardiac myocytes. Human EHTs started to show coherent contractions 5-10 days after casting, reached regular (mean 0.5 Hz) and strong (mean 100 µN) contractions for up to 8 weeks. They displayed a dense network of longitudinally oriented, interconnected and cross-striated cardiomyocytes. Spontaneous hEHT contractions were analyzed by automated video-optical recording and showed chronotropic responses to calcium and the β-adrenergic agonist isoprenaline. The proarrhythmic compounds E-4031, quinidine, procainamide, cisapride, and sertindole exerted robust, concentration-dependent and reversible decreases in relaxation velocity and irregular beating at concentrations that recapitulate findings in hERG channel assays. In conclusion this study establishes hEHT as a simple in vitro model for heart research.

Summary Aims To estimate Adult ADHD Self‐Report Scale (ASRS‐v1.1) Symptom Checklist normative total scores among the US adult general population and to evaluate overall attention‐deficit hyperactivity disorder (ADHD) symptom burden among US adults with ADHD. Methods Prior 2012 and 2013 US National Health and Wellness Survey respondents were re‐contacted. Demographics, comorbidities, and ASRS‐v1.1 data were collected. ASRS‐v1.1 scores were compared by sex, age, ADHD diagnosis, and ADHD medication use. Group differences were evaluated using chi‐square tests and independent samples t‐tests for categorical and continuous variables, respectively. Results Of 22 397 respondents, 465 self‐reported being diagnosed with ADHD by a physician; of these, 174 self‐reported using ADHD medication. The mean ASRS‐v1.1 total score was 2.0 (SD = 3.2); scores differed by age and sex (all, P < 0.001). ADHD (vs no ADHD) was associated with depression (58.1% vs 18.0%), anxiety (53.1% vs 16.0%), and sleep difficulties (37.0% vs 14.0%) (all, P < 0.001). ADHD medication use (vs no use) was associated with depression (68.4% vs 51.9%), anxiety (67.2% vs 44.7%), panic disorder (25.9% vs 17.2%), and insomnia (27.6% vs 19.6%) (all, P < 0.05). ADHD (vs no ADHD) respondents scored higher on all 18 ASRS‐v1.1 items (all, P < 0.05). Medication users (vs non‐users) scored higher on six items (all, P < 0.05). Discussion Adult ADHD may be undertreated or sub‐optimally treated, despite a high symptom burden. Normative data will allow comparisons with individuals’ scores to support the assessment of ADHD symptom burden among adults. Conclusion Findings highlight the importance of assessing ADHD symptom burden, especially among adults presenting with comorbidities.

Regional anesthesia techniques such as the ultrasound-guided PECS II (pectoral nerve block) block are increasingly employed to optimize perioperative analgesia while minimizing systemic anesthetic exposure. Ropivacaine is commonly used for its favorable pharmacological profile; however, clinical data on its pharmacokinetics and systemic metabolite behavior following interpectoral administration remain limited. This study aimed to characterize the plasma concentration–time profile of ropivacaine and its main active metabolite, 3-OH-ropivacaine, in patients undergoing interpectoral nerve block, using a validated LC-MS/MS (liquid chromatography coupled with mass spectrometry) method. Venous blood samples were collected from 18 patients at predefined time points (0, 1, 3, 6, and 24 h) following a PECS II block performed with a ropivacaine-lidocaine mixture. Plasma concentrations were quantified via a validated LC-MS/MS protocol in accordance with FDA (Food and Drug Administration) and EMA (European Medicines Agency) guidelines. Pharmacokinetic parameters were derived using non-compartmental analysis. Ropivacaine reached a mean peak plasma concentration (Cmax—maximum concentration) of 167.5 ± 28.3 ng/mL at 1.3 ± 0.2 h (Tmax—maximum time). The metabolite 3-OH-ropivacaine peaked at 124.1 ± 21.4 ng/mL at 2.3 ± 0.3 h. The terminal elimination half-life was 19.4 ± 2.8 h for ropivacaine and 29.2 ± 3.1 h for its metabolite. Plasma levels demonstrated prolonged systemic exposure with predictable pharmacokinetics. The PECS II block using ropivacaine results in sustained systemic levels of both the parent drug and its primary metabolite, supporting its role in prolonged perioperative analgesia. These data provide a pharmacokinetic foundation for personalized regional anesthesia protocols. This strategy facilitates the adaptation of anesthetic protocols to the individual characteristics of each patient, aligning with the principles of personalized medicine, particularly in patients with altered metabolic capacity.

Cardiac resynchronization therapy devices, implantable cardioverter defibrillators, and pacemakers are used to treat advanced systolic heart failure, ventricular tachyarrhythmias, and bradyarrhythmia. Over the past ten years, there has been a notable rise in the number of cardiac implanted electronic device implants because of mounting evidence of better survival and quality of life among specific patient populations. Appropriate analgesia and sedation throughout the implantation procedure is crucial for the patient’s stability. This paper aims to describe the advantages of both interpectoral plane block (PECS I) and interpecto-seratus plane block (PECS II) for the implantation of cardiac devices.Combining PECS I and PECS II blocks provides advantages for the thoracic wall procedures. While the PECS I block anesthetizes the medial and lateral pectoral nerves, PECS II extends coverage to upper intercostal nerves (T2-T7), as well as the long thoracic and thoracodorsal nerves, covering areas that are not anesthetize adequately by PECS I alone. Minimizing the need for opioids, leading to fewer opioid related side effects contributing to shorter recovery time and nonetheless creating less discomfort for the patient.This combined regional technique offers comfort to the patient due to its sole puncture needed for performance and by offering an extensive anesthesia at the site of the procedure.

Ropivacaine, a widely used regional anesthetic also used for pain management, has been increasingly used in recent years due to its increased efficacy and improved safety compared to similar anesthetics. Biomonitoring of ropivacaine and its metabolites during and after anesthesia is an essential process for ensuring therapeutic efficacy and safe usage for patients. The most useful biomonitoring tool in recent years has been liquid chromatography coupled with mass spectrometry (LC-MS/MS), which offers selectivity, sensitivity, as well as accuracy of measurements. The current manuscript summarizes and discusses the existing liquid chromatographic methods described in the literature, as well as the personal experience with developing bioanalytical and analytical methods for the quantification of ropivacaine in biological samples for clinical applications. It is focused on methodological aspects, recent advancements, challenges, and future perspectives, highlighting the importance of LC-MS/MS techniques in ropivacaine analysis.

Effective pain management is vital for critically ill patients, particularly post-surgery or trauma, as it can mitigate the stress response and positively influence morbidity and mortality rates. The suboptimal treatment of pain in Intensive Care Unit (ICU) patients is often due to a lack of education, apprehensions about side effects, and improper use of medications. Hence, the engagement of pain management and anesthesiology experts is often necessary. While opioids have been traditionally used in pain management, their side effects make them less appealing. Local anesthetics, typically used for anesthesia and analgesia in surgical procedures, have carved out a unique and crucial role in managing pain and other conditions in critically ill patients. This work aims to offer a comprehensive overview of the role, advantages, challenges, and evolving practices related to the use of local anesthetics in ICUs. The ability to administer local anesthetics continuously makes them a suitable choice for controlling pain in the upper and lower extremities, with fewer side effects. Epidural analgesia is likely the most used regional analgesic technique in the ICU setting. It is primarily indicated for major abdominal and thoracic surgeries, trauma, and oncology patients. However, it has contraindications and complications, so its use must be carefully weighed. Numerous challenges exist regarding critically ill patients, including renal and hepatic failure, sepsis, uremia, and the use of anticoagulation therapy, which affect the use of regional anesthesia for pain management. Appropriate timing and indication are crucial to maximizing the benefits of these methods. The advent of new technologies, such as ultrasonography, has improved the safety and effectiveness of neuraxial and peripheral nerve blocks, making them feasible options even for heavily sedated patients in ICUs.