Development and application of an advanced algorithm for environmental risk assessment and safety management of pesticide residues in agricultural soils: Monitoring of currently used pesticide in upland soils.

This study conducted the development of an advanced risk assessment algorithm system and safety management strategies using pesticide residue monitoring data from soils. To understand the status of pesticide residues in agricultural soils, monitoring was performed on 116 types of pesticides currently in use across 300 soil sites. The analysis of the monitoring results, alongside the physicochemical properties of the pesticides, led to the selection of soil half-life as a critical component in residue analysis. The use of Toxicity Exposure Ratio (TER) and Risk Quotient (RQ) for environmental risk assessment, based on monitoring data, presents limitations due to its single-component, conservative approach, which does not align with actual field conditions. Therefore, there is a necessity for a risk assessment process applicable in real-world scenarios. In this research, an efficient and accurate risk assessment algorithm system, along with a safety management model, was developed. Using the physicochemical properties of pesticides (such as soil half-life), monitoring results, and toxicity data, cluster analysis and Principal Component Analysis (PCA) validation identified four pesticides: boscalid, difenoconazole, fluquinconazole, and tebuconazole. The k-mean cluster analysis selected three priority management sites where the contribution of these four pesticides to the RQ was between 94-99 %, showing similar results to the RQ calculated for all pesticides. Predictions made with the developed model for the time required for soil half-life based RQ to drop below 1 at these priority sites showed only a 1-9 day difference between the four pesticides of concern and all pesticides, indicating comparable outcomes. The scenario of replacing high-risk pesticides with those of lower risk demonstrated that the RQ could be consistently maintained at about 50 % level. The results of this study suggest that through monitoring, evaluation, and management, effective and accurate environmental safety management of pesticides in soil can be achieved.

Radiographic Evaluation of Regenerative Endodontic Procedures and Apexification Treatments with the Assessment of External Root Resorption.

INTRODUCTION: This multi-centered cohort study evaluated the radiographic outcomes of regenerative endodontic procedures (REPs) and apexification treatments (APEX) of immature teeth with endodontic disease. MATERIALS AND METHODS: This cohort study included a retrospective record review and prospective data collection of pediatric patients with teeth treated with REPs or APEX between 2005-2014. Data including the presence of a periapical lesion, external root resorption (ERR), obliteration, apical hard tissue, apical closure, intracanal calcifications, and radiographic root area (RRA) change based on measurements were collected/measured from radiographic images. Univariate and multivariate analyses were conducted. RESULTS: The cohort included 190 subjects (204 teeth (92 REPs; 112 APEX)). The frequency of pre-treatment periapical pathology was similar between cases in which the clinical treatment failed versus successful treatment cases. However, the frequency of pre-treatment ERR was higher in failed cases than in successful cases (p=0.007). The mean RRA change was greater than twenty percent in 21% of the REPs cases. In traumatized teeth, REP treatment resulted in less hard tissue formation than other endodontic disease etiologies measured by RRA (p=0.001). 53% of cases with ERR (16/30) showed signs of healing/arrest and were mostly treated with REPs (11/16). CONCLUSIONS: The presence of ERR negatively affected the treatment outcome. There was significant variability in RRA change in REPs. Signs of healing/arrest of the resorptive lesion were radiographically visible in many cases treated with REPs.

Assessing the Utility of Acoustic Radiation Force Impulse in the Evaluation of Non-Alcoholic Fatty Liver Disease with Severe Obesity or Steatosis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) encompasses a heterogeneous spectrum ranging from simple steatosis to fibrosis and cirrhosis. Fibrosis, associated with long-term overall mortality and liver-related events, requires evaluation. Traditionally, liver biopsy has been the gold standard for diagnosing fibrosis. However, its invasive nature, potential complications, and sampling variability limit widespread use. Consequently, various non-invasive tests have been developed as alternatives for diagnosing fibrosis in NAFLD patients. AIM: This study aimed to compare the accuracy of non-invasive tests (NITs) and evaluate the diagnostic accuracy of acoustic radiation force impulse (ARFI), one of the point shear wave techniques, compared to conventional methods, assessing its effective role in diagnosis. METHODS: This is a retrospective study; a total of 136 patients diagnosed with fatty liver disease through ultrasonography were enrolled. The anthropometric data of the patients were collected on the day of admission and blood tests, measurements of ARFI, and a point shear test were conducted using abdominal ultrasound; a biopsy was performed the following day. In addition, we calculated the aspartate aminotransferase-to-platelet ratio index (APRI) index based on four factors (FIB-4) and the NAFLD fibrosis score (NFS). Subsequently, we assessed the diagnostic accuracy of NITs within various subgroups based on the extent of obesity, steatosis, or NAFLD activity score. RESULTS: ARFI has been shown to have the highest diagnostic value among various NITs, with AUROC values of 0.832, 0.794, 0.767, and 0.696 for ARFI, APRI, FIB-4, and NFS, respectively. In the morbidly obese subgroup, the AUROC values of ARFI, APRI, FIB-4, and NFS were 0.805, 0.769, 0.736, and 0.674. In the group with severe steatosis or non-alcoholic steatohepatitis (NASH), the AUROC values were 0.679, 0.596, 0.661, and 0.612, respectively, for severe steatosis and 0.789, 0.696, 0.751, and 0.691, respectively, for NASH. CONCLUSIONS: In conclusion, ARFI is not affected by various factors and maintains diagnostic accuracy compared to serum NITs. Therefore, we can recommend ARFI as a valuable diagnostic test to screen for advanced fibrosis in patients with NAFLD.

Outcomes-Based Treatment Planning in Endodontics: Applying the Latest Evidence.

A comprehensive understanding of the factors that influence treatment outcomes is crucial in endodontic diagnosis and treatment planning. Having knowledge that takes into account dental and patient-related conditions when choosing procedures can help clinicians maximize the prognosis of natural teeth and reduce postoperative complications. That being said, the landscape of outcome studies in endodontics is continually evolving, presenting a challenge for many clinicians trying to stay current with the latest literature. This article reviews factors that influence the outcomes of the following endodontic therapies: primary root canal treatment, nonsurgical retreatment, and surgical retreatment. An emphasis is placed on the importance of considering preoperative and treatment-related factors as prognostic indicators before developing a treatment plan, with the ultimate goal of enhancing tooth durability and ensuring patient satisfaction.

Saving Cracked Teeth: The Current State of Evidence.

Treatment planning for cracked teeth can be quite challenging for clinicians, as various outcomes-related clinical parameters must be considered. Historically, extraction was recommended for cracked teeth with radicular extensions due to their poor prognosis. Recent literature, however, suggests that these teeth may be saved with careful case selection and appropriate treatment. This article closely examines Davis and Shariff's 2019 study, which demonstrated a promising prognosis for treating cracked teeth with radicular extensions following a specific treatment protocol. This literature review discusses current findings regarding cracked teeth and suggested treatment modalities to optimize outcomes.

The Anti-Inflammatory Effect of SDF-1 Derived Peptide on Porphyromonas gingivalis Infection via Regulation of NLRP3 and AIM2 Inflammasome.

(1) Background: Peptides are appealing as pharmacological materials because they are easily produced, safe, and tolerable. Despite increasing gum-care awareness, periodontitis is still prevalent and is influenced by factors like high sugar consumption, smoking, and aging. Porphyromonas gingivalis is considered a major etiologic agent of periodontitis and activates the NLR family pyrin domain containing 3 (NLRP3) but is absent in melanoma 2 (AIM2) inflammasomes, resulting in pro-inflammatory cytokine release. (2) Methods: We examined the anti-inflammatory effects of 18 peptides derived from human stromal cell-derived factor-1 (SDF-1) on THP-1 macrophages. Inflammation was induced by P. gingivalis, and the anti-inflammatory effects were analyzed using molecular biological techniques. In a mouse periodontitis model, alveolar bone resorption was assessed using micro-CT. (3) Results: Of the 18 SDF-1-derived peptides, S10 notably reduced IL-1ß and TNF-α secretion. S10 also diminished the P. gingivalis-induced expression of NLRP3, AIM2, ASC (apoptosis-associated speck-like protein), caspase-1, and IL-1ß. Furthermore, S10 attenuated the enhanced TLR (toll-like receptor) signaling pathway and decreased the phosphorylation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). In addition, S10 mitigated alveolar bone loss in our P. gingivalis-induced mouse model of periodontitis. (4) Conclusions: S10 suppressed TLR/NF-κB/NLRP3 inflammasome signaling and the AIM2 inflammasome in our P. gingivalis-induced murine periodontitis model, which suggests that it has potential use as a therapeutic treatment for periodontitis.

BRD2-specific inhibitor, BBC0403, inhibits the progression of osteoarthritis pathogenesis in osteoarthritis-induced C57BL/6 male mice.

BACKGROUND AND PURPOSE: The discovery of new bromo- and extra-terminal inhibitors presents new drugs to treat osteoarthritis (OA). EXPERIMENTAL APPROACH: The new drug, BBC0403, was identified in the DNA-encoded library screening system by searching for compounds that target BRD (bromodomain-containing) proteins. The binding force with BRD proteins was evaluated using time-resolved fluorescence energy transfer (TR-FRET) and binding kinetics assays. Subsequently, in vitro and ex vivo analyses demonstrated the effects of the BRD2 inhibitor, BBC0403, on OA. For animal experiments, medial meniscus destabilization was performed to create a 12-week-old male C57BL/6 mouse model, and intra-articular (i.a.) injections were administered. Histological and immunohistochemical analyses were then performed. The underlying mechanism was confirmed by gene set enrichment analysis (GSEA) using RNA-seq. KEY RESULTS: TR-FRET and binding kinetics assays revealed that BBC0403 exhibited higher binding specificity for BRD2 compared to BRD3 and BRD4. The anti-OA effects of BBC0403 were tested at concentrations of 5, 10 and 20 µM (no cell toxicity in the range tested). The expression of catabolic factors, prostaglandin E2 (PGE2) production and extracellular matrix (ECM) degradation was reduced. Additionally, the i.a. injection of BBC0403 prevented OA cartilage degradation in mice. Finally, BBC0403 was demonstrated to suppress NF-κB and MAPK signalling pathways. CONCLUSION AND IMPLICATIONS: This study demonstrated that BBC0403 is a novel BRD2-specific inhibitor and a potential i.a.-injectable therapeutic agent to treat OA.

Dihydrostilbenes and flavonoids from whole plants of Jacobaea vulgaris.

The isolation of previously undescribed 12 compounds from the MeOH extract of Jacobaea vulgaris whole plants is disclosed, comprising 11 dihydrostilbenes (1-11) and one flavanone (12), and eight known compounds (six flavonoids, one dihydrostilbene, and one caffeoylquinic acid). Structural elucidation employed spectroscopic methods, including 1D and 2D NMR spectroscopy, HRESIMS, and ECD calculations. Evaluation of the compounds' effects on PCSK9 and LDLR mRNA expression revealed that compounds 1 and 3 downregulated PCSK9 mRNA while increasing LDLR mRNA expression, suggesting potential cholesterol-lowering properties.

Efficient Combination Chemo-Sonodynamic Cancer Therapy Using Mitochondria-Targeting Sonosensitizer-Loaded Polysorbate-Based Micelles.

Sonodynamic therapy (SDT), utilizing ultrasound (US) and sonosensitizers, holds immense potential as a noninvasive and targeted treatment for a variety of deep-seated tumors. However, the clinical translation of SDT is hampered by several key limitations in sonosensitizers, especially their low aqueous stability and poor cellular uptake. In this study, non-ionic polysorbate (Tween 80, T80) was adopted to formulate effective nanocarriers for the safe and efficient delivery of sonosensitizers to cancer cells. Mitochondria-targeting triphenylphosphonium (TPP)-conjugated chlorin e6 (Ce6) sonosensitizer was loaded into T80-based micelles for efficient SDT. Pro-oxidant piperlongumine (PL) was co-encapsulated with TPP-conjugated Ce6 (T-Ce6) in T80 micelles to enable combination chemo-SDT. T80 micelles substantially enhanced the cellular internalization of T-Ce6. As a result, T80 micelles loaded with T-Ce6 and PL [T80(T-Ce6/PL)] significantly elevated intracellular reactive oxygen species (ROS) generation in MCF-7 human breast cancer cells upon US exposure. Moreover, T-Ce6 exhibited selective accumulation within the mitochondria, leading to efficient cell death under US irradiation. Importantly, T80(T-Ce6/PL) micelles caused cancer-specific cell death by selectively triggering apoptosis in cancer cells through PL. This study demonstrated the feasibility of using T80(T-Ce6/PL) micelles for efficient and cancer-specific combination chemo-SDT.

Arterial Distension Monitoring Scheme Using FPGA-Based Inference Machine in Ultrasound Scanner Circuit System.

This paper presents an arterial distension monitoring scheme using a field-programmable gate array (FPGA)-based inference machine in an ultrasound scanner circuit system. An arterial distension monitoring requires a precise positioning of an ultrasound probe on an artery as a prerequisite. The proposed arterial distension monitoring scheme is based on a finite state machine that incorporates sequential support vector machines (SVMs) to assist in both coarse and fine adjustments of probe position. The SVMs sequentially perform recognitions of ultrasonic A-mode echo pattern for a human carotid artery. By employing sequential SVMs in combination with convolution and average pooling, the number of features for the inference machine is significantly reduced, resulting in less utilization of hardware resources in FPGA. The proposed arterial distension monitoring scheme was implemented in an FPGA (Artix7) with a resource utilization percentage less than 9.3%. To demonstrate the proposed scheme, we implemented a customized ultrasound scanner consisting of a single-element transducer, an FPGA, and analog interface circuits with discrete chips. In measurements, we set virtual coordinates on a human neck for 9 human subjects. The achieved accuracy of probe positioning inference is 88%, and the Pearson coefficient (r) of arterial distension estimation is 0.838.

Solution-processed Sb2Se3 photocathodes under Se-rich conditions and their photoelectrochemical properties.

In this study, selenium (Se)-rich antimony selenide (Sb2Se3) films were fabricated by applying a solution process with the solvents ethylenediamine and 2-mercaptoethanol to optimize the photoelectrochemical (PEC) performance of the Sb2Se3 photocathode. Various antimony (Sb)-Se precursor solutions with different molar ratios of Sb and Se (Sb : Se = 1 : 1.5, 1 : 3, 1 : 4.5, 1 : 7.5, and 1 : 9) were prepared to attain Se-rich fabrication conditions. As a result, the Se-rich Sb2Se3 films fabricated using the Sb-Se precursor solution with a molar ratio of Sb : Se = 1 : 7.5 exhibited an improved PEC performance, compared to the stoichiometric Sb2Se3 film. The charge transport was improved by the abundant Se element and thin selenium oxide (Se2O3) layer in the Se-rich Sb2Se3 film, resulting in a decrease in Se vacancies and substitutional defects. Moreover, the light utilization in the long wavelength region above 800 nm was enhanced by the light-trapping effect because of the nanowire structure in the Se-rich Sb2Se3 film. Hence, the optimal Se-rich Sb2Se3 photocathodes showed an improved photocurrent density of -0.24 mA cm-2 at the hydrogen evolution reaction potential that was three times higher than that of the stoichiometric Sb2Se3 photocathodes (-0.08 mA cm-2).

Key Strategies on Cu2O Photocathodes toward Practical Photoelectrochemical Water Splitting.

Cuprous oxide (Cu2O) has been intensively in the limelight as a promising photocathode material for photoelectrochemical (PEC) water splitting. The state-of-the-art Cu2O photocathode consists of a back contact layer for transporting the holes, an overlayer for accelerating charge separation, a protection layer for prohibiting the photocorrosion, and a hydrogen evolution reaction (HER) catalyst for reducing the overpotential of HER, as well as a Cu2O layer for absorbing sunlight. In this review, the fundamentals and recent research progress on these components of efficient and durable Cu2O photocathodes are analyzed in detail. Furthermore, key strategies on the development of Cu2O photocathodes for the practical PEC water-splitting system are suggested. It provides the specific guidelines on the future research direction for the practical application of a PEC water-splitting system based on Cu2O photocathodes.

Corrigendum: Transcriptional inhibition of STAT1 functions in the nucleus alleviates Th1 and Th17 cell-mediated inflammatory diseases.

[This corrects the article DOI: 10.3389/fimmu.2022.1054472.].

Identification of Mitral Valve Prolapse on Non-electrocardiography-gated Enhanced Chest Computed Tomography.

PURPOSE: The primary imaging modality for the diagnosis of mitral valve prolapse (MVP) is echocardiography supplemented by electrocardiography (ECG)-gated cardiac computed tomography (CT) angiography. However, we have recently encountered patients with MVP who were initially identified on non-ECG-gated enhanced chest CT. The purpose of this study is to evaluate the diagnostic accuracy of non-ECG-gated enhanced chest CT to predict the presence of MVP. PATIENTS AND METHODS: Of 92 patients (surgically confirmed MVP who underwent non-ECG-gated chest CT), 27 patients were excluded for motion artifact or insufficient surgical correlation, and 65 patients were ultimately included. As a control, 65 patients with dyspnea and without MVP (non-ECG-gated chest CT and echocardiography were performed within 1 month) were randomly selected. We retrospectively analyzed an asymmetric double line sign on axial CT images for the presence of MVP. The asymmetric double line sign was defined as the presence of a linear structure, not located in the plane traversing the mitral annulus. RESULTS: Use of the asymmetric double line sign to predict MVP on non-ECG-gated CT showed modest sensitivity, high specificity, modest negative predictive value, and high positive predictive value of 59% (38/65), 99% (64/65), 70% (64/91), and 97% (38/39), respectively. CONCLUSION: The asymmetric double line sign on non-ECG-gated enhanced chest CT may be a valuable finding to predict the presence of MVP. Familiarity with this CT finding may lead to prompt diagnosis and proper management of MVP.

Novel molecule BBC0901 inhibits BRD4 and acts as a catabolic regulator in the pathogenesis of osteoarthritis.

Osteoarthritis (OA) is induced by matrix degradation and inflammation mediated by bromo-domain-containing protein 4 (BRD4)-dependent catabolic factors. BRD4 acts as both a transcriptional regulator and an epigenetic reader. BBC0901 was identified as an inhibitor of BRD4 using a DNA-encoded library screening system. We aimed to demonstrate the effects of BBC0901 on OA pathogenesis by in vitro, ex vivo, and in vivo analyses. BBC0901 inhibited the expression of catabolic factors that degrade cartilage without significantly affecting the viability of mouse articular chondrocytes. Additionally, ex vivo experiments under conditions mimicking OA showed that BBC0901 suppressed extracellular matrix degradation. RNA sequencing analysis of gene expression patterns showed that BBC0901 inhibited the expression of catabolic factors, such as matrix metalloproteinases (MMPs) and cyclooxygenase (COX)2, along with reactive oxygen species (ROS) production. Furthermore, intra-articular (IA) injection of BBC0901 into the knee joint blocked osteoarthritic cartilage destruction by inhibition of MMP3, MMP13, COX2, interleukin (IL)6, and ROS production, thereby obstructing the nuclear factor kappa-light-chain-enhancer of activated B cell and mitogen activated protein kinase signaling. In conclusion, BBC0901-mediated BRD4 inhibition prevented OA development by attenuating catabolic signaling and hence, can be considered a promising IA therapeutic for OA.

Acyclic Triterpenoids from Alpinia katsumadai Seeds with Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Secretion Inhibitory Activity.

Cholesterol is one of the primary causes of cardiovascular disease. Investigating and developing potential drugs to effectively treat hypercholesterolemia are therefore of critical importance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been developed to lower the levels of low-density lipoprotein cholesterol in patients with hypercholesterolemia. In this study, we aimed to identify compounds that inhibit the PCSK9 mRNA expression and secretion. The bioassay-guided investigation of Alpinia katsumadai seeds utilizing a PCSK9 mRNA expression monitoring assay yielded the isolation and identification of seven new compounds. Among these were three acyclic triterpenoids (1-3), an acyclic sesquiterpenoid (5), one arylpentanoid (6), and two diarylheptanoids (7 and 8), alongside 10 known compounds. The structures of these compounds were determined using nuclear magnetic resonance (NMR) spectroscopy, vibrational circular dichroism (VCD), and electronic circular dichroism (ECD). The absolute configurations of compounds 1 and 2 were identified by comparing the calculated and experimental VCD data as the ECD method was unable to distinguish the diastereomers. All the isolated compounds were evaluated for their regulatory effects on the low-density lipoprotein receptor (LDLR) and PCSK9 mRNA expression, as well as PCSK9 secretion. Of the tested compounds, two of the acyclic triterpenoids (1 and 2) demonstrated potent effects in downregulating PCSK9 at both the mRNA and protein levels, compared with the positive control (berberine chloride). Additionally, compound 1 inhibited PCSK9 secretion to a level comparable to that of berberine chloride. This study identifies compounds that inhibit PCSK9 mRNA expression and secretion, offering significant contributions to the development of novel drugs for the effective treatment of hypercholesterolemia..

Stereochemical assignment of clerodane-type diterpenes from the fruits of Casearia grewiifolia and their ability to inhibit PCSK9 expression.

More than 20 natural products have been reported to modulate PCSK9-mediated cholesterol regulation, and small-molecule-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors continue to be developed and identified. Here, twelve undescribed clerodane-type diterpenes (1-9 and 12-14) and two known compounds were isolated from the chloroform-soluble extract of the dried fruits of Casearia grewiifolia Vent. using a PCSK9 mRNA expression monitoring assay. Among the undescribed compounds, the stereochemistry of two diastereomeric grewiifolins A and B (1 and 2) were extensively elucidated using 2D Nuclear Overhauser Effect Spectroscopy (NOESY) experiments, excitation-sculptured indirect detection experiments (EXSIDE), interproton distance analyses, and computational calculations that included quantum chemical shift calculations combined with DP4+ analysis. All isolates were assessed for their inhibitory activity against PCSK9 and IDOL mRNA expression. Among the compounds tested, compound 3 inhibited PCSK9 and IDOL mRNA expression.

Impact of Sarcopenia on Percutaneous Epidural Balloon Neuroplasty in Patients with Lumbar Spinal Stenosis: A Retrospective Analysis.

Background and Objectives: With the aging population, the incidence of degenerative lumbar spinal stenosis (LSS) is increasing. Sarcopenia is an age-related muscular decrease. Although epidural balloon neuroplasty is effective in patients with LSS refractory to conventional treatments, its effect has not been assessed in patients with sarcopenia. Therefore, this study evaluated the effect of epidural balloon neuroplasty in patients with LSS and sarcopenia. Materials and Methods: This retrospective study reviewed the following details from the electronic medical records: patient characteristics, including sex, age, body mass index, diabetes, hypertension, stenosis grading, pain duration, location, pain intensity, and medications. Back and leg pain intensity was evaluated before and after the procedure at one, three, and six months during the follow-up period. A generalized estimating equations model was used at six months follow-up. Patients were divided into sarcopenia and non-sarcopenia groups using the cross-sectional area of the psoas muscle at the level of L3 on magnetic resonance imaging. Results: A total of 477 patients were included (sarcopenia group: 314 patients, 65.8%; non-sarcopenia group: 163 patients, 34.2%). Age, sex, body mass index, and medication quantification scale III were statistically different between both groups. The generalized estimating equations analyses-with unadjusted and adjusted estimation-revealed a significantly reduced pain intensity after the procedure compared to the baseline in both groups. The difference in pain intensity between both groups was not statistically different. Conclusions: Percutaneous epidural balloon neuroplasty may be considered for patients with chronic lumbar LSS regardless of accompanying sarcopenia.

Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins.

Targeting aberrant epigenetic programs that drive tumorigenesis is a promising approach to cancer therapy. DNA-encoded library (DEL) screening is a core platform technology increasingly used to identify drugs that bind to protein targets. Here, we use DEL screening against bromodomain and extra-terminal motif (BET) proteins to identify inhibitors with new chemotypes, and successfully identified BBC1115 as a selective BET inhibitor. While BBC1115 does not structurally resemble OTX-015, a clinically active pan-BET inhibitor, our intensive biological characterization revealed that BBC1115 binds to BET proteins, including BRD4, and suppresses aberrant cell fate programs. Phenotypically, BBC1115-mediated BET inhibition impaired proliferation in acute myeloid leukemia, pancreatic, colorectal, and ovarian cancer cells in vitro. Moreover, intravenous administration of BBC1115 inhibited subcutaneous tumor xenograft growth with minimal toxicity and favorable pharmacokinetic properties in vivo. Since epigenetic regulations are ubiquitously distributed across normal and malignant cells, it will be critical to evaluate if BBC1115 affects normal cell function. Nonetheless, our study shows integrating DEL-based small-molecule compound screening and multi-step biological validation represents a reliable strategy to discover new chemotypes with selectivity, efficacy, and safety profiles for targeting proteins involved in epigenetic regulation in human malignancies.